- Industrial preparation method of AZD9291
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The invention relates to a preparation method of AZD9291, which comprises the following steps: by using N2 [[2 (dimethylamino) ethyl] methylamino] 4methoxy5 [[4 (1methyl1Hindole 3yl) 2pyrimidinyl] amino] aniline and acrylic acid as raw materials, an alcohol reagent as a reaction solvent, a hierarchical pore molecular sieve as a catalyst and petroleum ether as a water-carrying agent, reacting to obtain AZD9291.
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Paragraph 0031-0042
(2021/03/03)
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- Method for industrially synthesizing AZD9291
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The invention relates to a preparation method of AZD9291. Thepreparation method of AZD9291 comprises the steps of taking N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline and acrylic acid as raw materials, taking an alcohol reagent as a reaction solvent, taking a hierarchical pore ZSM-5 molecular sieve as a catalyst, andtaking petroleum ether as a water carrying agent to react to obtain the AZD9291.
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Paragraph 0035-0042
(2021/02/13)
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- Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib
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Osimertinib, a third generation potent and specific EGFR inhibitor is an important drug against many forms of cancer. It was synthesized by an improved and highly efficient protocol, revisiting the classical synthetic process and modifying parameters, such as solvents, temperature, reagents, and reaction time. A cost-effective, environmentally friendly methodology for the synthesis of osimertinib was established, which gave shorter reaction times, saved labor by eliminating purification steps through column chromatography, and enhanced yields. Four of the seven steps in total, were proceeded quantitatively or almost quantitatively (ca. 98 %). This synthetic protocol provides a very high overall yield, up to 68 %. In addition, the entire approach enables the preparation of osimertinib analogues and could be extended in the synthesis of other structurally similar bioactive compounds.
- Alivertis, Dimitrios,Skobridis, Konstantinos,Voulgari, Pinelopi
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- Compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase and application thereof
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The invention discloses a compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase, and is characterized in that the structural formula is as follows. Among them: Substituent R1 . One of: Substituent R2 . One of: The substituent X is H or Cl. Substituent R3 To H. One of the following.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF OSIMERTINIB MESYLATE
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The present invention relates to an improved process for the preparation of Osimertinib mesylate with high purity and high yield.
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- Osimertinib dimer, preparation method and application thereof
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The invention belongs to the field of medicines, and particularly relates to an osimertinib dimer, a preparation method and application thereof, and the chemical structure of the osimertinib dimer isshown as the specification. The osimertinib dimer is synthesized by taking a compound 1 as a starting material, acrylic anhydride and acrylic acid are gradually added according to a synthesis route inthe intermediate reaction process, and the osimertinib dimer is prepared through reduction, acylation, addition and condensation, and the preparation method is simple, convenient to operate, low in equipment condition requirement, extremely easy to implement, and simple in aftertreatment. The osimertinib dimer synthesized by the preparation method is high in purity, can be used as an impurity reference substance to be applied to qualitative and quantitative research and detection of osimertinib impurities, and has important significance in effectively controlling the quality of osimertinib.
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- Method for synthesizing osimertinib by molecular sieve catalysis
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The invention relates to the field of organic synthesis, in particular to a novel method for synthesizing osimertinib through molecular sieve catalysis. N-1-[2-(dimethylamino) ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indole-3-yl-2-pyrimidinyl]-1,2,4-triaminobenzene and acrylic acid as raw materials, acrylic acid is added into an alcohol solvent, reaction is carried out through molecular sievecatalysis and microwave heating, and after the reaction is completed, post-treatment is carried out to obtain the osimertinib. According to the method, the reaction conditions are mild, industrial production is facilitated, the raw materials are environmentally friendly in use, used highly toxic raw materials are decreased, the yield is high, and the reaction efficiency is high.
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Paragraph 0027-0042
(2019/10/23)
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- Synthetic method of osimertinib AZD9291
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The invention provides a synthetic method of osimertinib AZD9291; an intermediate (III) is synthesized by adopting CoCl2/SoCl2 to catalyze; an intermediate (VIII) is synthesized by adopting CoSO4.7H2Oto carry out catalytic reduction; in the preparation of an intermediate (X), sodium carbonate is used as an acid binding agent; and the intermediate (X) and methane sulfonic acid are adopted for salification in a mixed solvent of ethyl alcohol and isopropyl alcohol to prepare the AZD9291. The synthetic method provided by the invention is high in yield, mild in reaction condition, simple in after-treatment and suitable for industrial production.
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- 2-(2, 4, 5-substituted aniline) pyrimidine derivative
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The invention relates to a 2-(2, 4, 5-substituted aniline) pyrimidine derivative, and more specifically discloses a compound represented by formula I or a pharmaceutically acceptable salt thereof, anda preparation method and applications of the compound represented by formula I and the pharmaceutically acceptable salt of the compound, wherein R1 to R9 are used for representing groups defined in the invention.
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Paragraph 0547-0552
(2019/11/21)
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- Osimertinib intermediate and preparation method thereof
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The invention belongs to the field of medicine synthesis and particularly relates to an osimertinib intermediate and a preparation method thereof. The provided osimertinib intermediate is a compound in a formula C and has a structural formula in the description, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl. After the compound in the formula C is hydrolyzed, the compound and a compound in a formula E are subjected to a condensation reaction, a compound in a formula F is prepared, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl.
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- AZD9291 Intermediate and preparation method of AZD9291
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The invention discloses AZD9291 intermediate and a preparation method of AZD9291. AZD9291 has a chemical name of N-{2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl}prop-2-enamide. The preparation method has a simple process, the raw material is easy to obtain and is economical and environmentally friendly, product yield and purity are high, the preparation method is easy to industrialize, lower in production cost and suitable for batch production, and the novel intermediate and the preparation method thereof are significant to AZD9291 economic techniques.
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- Preparation method of highly selective EGFR mutant inhibitor AZD9291
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The invention discloses a preparation method of a highly selective EGFR mutant inhibitor AZD9291. The chemical name of the highly selective EGFR mutant inhibitor AZD9291 is N-{2-[[2-(dimethylamino)ethly]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indole-3-group)-2-pyrimidyl] amino]phenyl}-2-acrylamide, the chemical formula is C28H33N7O2, and the structural formula is shown in the description. The preparation process is simple, raw materials are easy to obtain, the method is economical and environmentally friendly, industrialization is easily achieved, the economic and technological development of drugs using AZD9291 as a raw material can be promoted, the production cost is reduced, and AZD9291 is suitable for large-batch production.
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- Preparation method for osimertinib mesylate
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The invention discloses a preparation method for osimertinib mesylate. The chemical name of osimertinib mesylate is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2-yl)amino)phenyl)acrylamide mesylate (AZD9291), and the chemical formula is C28H33N7O2.CH4O3S. The process of the preparation technique of the preparation method is simple, materials areeasy to obtain, and the preparation method is cost-efficient and environment-friendly, can help realize industrialization, can promote the economic and technological development of osimertinib activeingredients, reduces production cost, and is suitable for mass production.
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- Synthesis process of osimertinib
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The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis process of osimertinib. The synthesis process comprises the following steps: performing palladium-carbon hydrogenation reduction on an intermediate (3) which is served as a raw material, and after reduction is completed, pumping out hydrogen and blowing in nitrogen and completely isolating the nitrogen from the air; adding acrylic acid into reaction liquid, adding acryloyl chloride and organic alkali, and performing reaction to obtain a product. According to the process, reduction and acylation are performed in the same reaction system, so that not only is the problem of intermediate amine instability effectively solved, but also the whole synthesis process is efficient, economic and environment-friendly; reduction and acylation reaction of the intermediate (3) is implemented by virtue of a one-pot strategy: palladium-carbon hydrogenation reduction is performed on nitryl, then acylation reaction is directly performed under the condition of isolating the air without any post-treatment, and the two reaction steps are finished in a pot; a one-pot method for multiple reaction steps is utilized for the first time to implement synthesis of the osimertinib.
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Paragraph 0026; 0027; 0028; 0029; 0030
(2018/04/01)
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- Pyrimidine heterocyclic compounds, preparation method and application thereof
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The present invention relates to compounds of a formula (I) shown in the description, and pharmaceutically acceptable salts, prodrugs and solvates thereof, and the compounds are useful for treating cancer and inflammation in mammals. The invention also discloses a preparation method for the compounds of the formula (I) and a pharmaceutical composition containing the compound.
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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The invention discloses a compound shown as a formula (I) or a salt acceptable to a drug thereof, a method for preparing the compound shown as the formula (I) or the salt acceptable to the drug thereof, a pharmaceutical composition containing the compound shown as the formula (I) or the salt acceptable to the drug thereof and applications for the compound shown as the formula (I) or the salt acceptable to the drug thereof. The structural formula of the compound is shown as the description, wherein R1, R2 and R3 are defined as the invention.
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Paragraph 0244-0247
(2019/01/06)
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- Osimertinib preparation method
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The present invention relates to an osimertinib preparation method, which comprises: (1) carrying out a nucleophilic substitution reaction on 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole and 4-fluoro-2-methoxy-5-nitroaniline to prepare a compound 1; (2) carrying out a substitution reaction on the compound 1 and N,N,N-trimethylethylenediamine in the presence of an organic alkali to prepare a compound 2; (3) reducing the compound 2 in the presence of a reducing agent to prepare a compound 3; (4) carrying out condensation on the compound 3 and 3-chloropropionyl chloride in the presence of an alkali to obtain a compound 4; (5) carrying out a heat elimination reaction on the compound 4 through heating in the presence of an alkali to prepare a compound 5; and (6) carrying out salification on the compound 5 and methanesulfonic acid under a heating condition to obtain osimertinib. According to the present invention, the osimertinib synthesis process has characteristics of stability, controllability, no high-toxicity solvent is used, energy saving and environmental protection.
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Paragraph 0068; 0069; 0070
(2018/10/27)
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- Preparation method of antitumor drug AZD9291
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The invention relates to a preparation method of an antitumor drug AZD9291. The preparation method comprises the following steps: taking 2-bromo-4-anisidine as a starting raw material; carrying out nitration reaction, grignard reaction, acylation reaction, reduction reaction, grignard reaction and elimination reaction to obtain AZD9291 free alkali. The preparation method disclosed by the inventionhas the beneficial effects of wide source of raw materials, low cost, simple operation, recyclable application of a solvent, low discharge amount of waste liquid, high recovery rate of a product andthe like, and easily realizes industralization.
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Paragraph 0031
(2018/07/30)
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- Preparation method of antitumor drug AZD9291
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The invention discloses a preparation method of antitumor drug AZD9291. The method is as follows: reaction of 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-pyrimidine-4-yl)-1-methylindole to obtain an intermediate 1; reaction of the intermediate 1 and N, N, N '-trimethylethylenediamine to obtain a compound intermediate 2; hydrogenation reduction of the intermediate 2 to obtain a compound intermediate 3, further introduction of acryloyl group into the intermediate 3 to obtain the AZD9291, and the method is characterized in that activator cuprous bromide is added into the preparing process of the intermediate 2; palladium carbon is used for catalytic hydrogenation reduction, and a mixed anhydride solution of acrylic acid is used for introduction of the acryloyl group of the AZD9291. The method effectively reduces waste solid generation, and improves the purity and the yield of the product.
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Paragraph 0060; 0061; 0063; 0064
(2017/12/02)
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- Method for preparing AZD9291
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The invention discloses a method for preparing AZD9291, and belongs to the technical field of medicine preparation. The method comprises the following steps: by taking 3-(2-chloro-pyrimidine-4-yl)-1-methylindole as a raw material, firstly, performing substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline so as to generate 3-[2-[(4-fluorine-2-methoxy-5-nitro)aniline]pyrimidine-4-yl]-1-methylindole (3); secondly, under the action of a catalyst, performing substitution on the compound 3 with N,N,N'-trimethyl quadrol so as to generate 3-[2-[(4-(N,N,N'-trimethylethylenediamine)-2-methoxy-5-nitro)aniline]pyrimidine-4-yl]-1-methylindole (5); performing reduction of nitro and amidation of amino on the compound 5, and performing synthesis by using a 'one-pot method', thereby obtaining AZD9291. The method is concise in process, environmentally friendly, low in cost and applicable to industrial production.
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Paragraph 0020; 0023
(2017/08/29)
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- Osimertinib mesylate preparation method
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The invention discloses an osimertinib mesylate preparation method. The method includes: subjecting 2-chloropyrimidine-4(3H)-ketone and 4-fluoro-2-methoxy-5-nitroaniline to substitution reaction; subjecting obtained 2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyridine-4(3H)-ketone and N,N,N'-trimethyl ethylenediamine to substitution reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-nitrophenylamino)pyridine-4(3H)-ketone to nitro reduction reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)pyridine-4(3H)-ketone to chlorination; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)-4-choropyridine and 1-methyl-1H-indol to condensation reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)-4-(1-methyl-1H-indol-3-yl)pyridine and acryloyl chloride to amidation; finally performing salt forming reaction to obtain osimertinib mesylate. The osimertinib mesylate preparation method is reasonable and concise in process route, simplified in operation and low in cost and is an environment-friendly method suitable for industrial production.
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- Preparation method of AZD9291
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The invention relates to the technical field of organic synthesis and bulk drug preparation and concretely relates to a preparation method of an antineoplastic drug AZD9291. 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N, N, N'-trimethylethylenediamine undergo a reaction to produce 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine, the 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine and 1-(1-methylindolyl-3-yl)-3-(dimethylamino)-2-acrylketone undergo a reaction to produce N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methylindolyl-3-yl)pyrimidin-2-yl)-2-nitrophenyl-1, 4-diamine, the N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methylindolyl-3-yl)pyrimidin-2-yl)-2-nitrophenyl-1, 4-diamine is hydrogenated until a nitro group is reduced to form an amino group, and the hydrogenated product and acryloyl chloride undergo a reaction to produce AZD9291.
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- New and Convergent Synthesis of Osimertinib
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New and convergent synthetic route of osimertinib is described on a dozen of grams scale. A key cyclization of 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine and 3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)prop-2-en-1-one is adopted to give the 4-(1H-indol-3-yl)-N-phenylpyrimidin-2-amine structure. Osimertinib is prepared in 40.4% yield over six steps and 99.1% purity (HPLC). Purification methods of the intermediates involved in the route are also given.
- Zhu, Guoqing,Wang, Xingyan,Wang, Feng,Mao, Yongjun,Wang, Han
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p. 2898 - 2901
(2017/09/26)
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- Intermediate used for AZD9291 preparation, and preparation method and application thereof
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The invention relates to the technical field of organic synthesis and raw medicine preparation, and concretely relates to an organic intermediate used for antitumor medicine AZD9291 preparation, and a preparation method and an application thereof. The intermediate is 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine. The preparation method of the intermediate comprises the following steps: 1, reacting 2-methoxy-4-fluoro-5-nitroaniline with cyanamide to obtain 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine; and 2, carrying out a nucleophilic substitution reaction on the 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N,N,N'-trimethylethylenediamine to prepare the 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine. The preparation method of the intermediate has the advantages of easily available raw materials, mild reaction conditions, simplicity and convenience in post-treatment, suitableness for amplified preparation, and high yield.
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- Anti-tumor drug synthesis method
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The invention relates to a synthetic method of an anti-tumor medicine, namely N-[2-[[2-(dimethylamino) ethyl] methyl amino]-4-methoxy-5-[[4-(1-methyl-1H-indole-3-yl)-2-pyrimidyl] amino] phenyl]-2-acrylamide (AZD9291) and a key intermediate of the anti-tumor medicine. The synthetic method comprises the following steps: performing Boc acid anhydride protection on 4-fluoro-2-methoxy-5-nitroaniline to obtain 4-fluoro-2-methoxy-5-nitroanilino tert-butyl formate, then reacting with N,N,N'-trimethylethylenediamine to obtain 4-(N,N,N'-trimethylethylenediamino)-2-methoxy-5-nitroanilino tert-butyl formate, then reducing to obtain 2-(N,N,N'-trimethylethylenediamino)-4-methoxy-5-tert-butyl carbamate phenylamine, then completely reacting with acryloyl chloride and directly removing a Boc protecting group to obtain 2-methoxy-4-N,N,N'-trimethylethylenediamino-5-acrylamido phenylamine, and finally reacting with 3-(2-chloropyrimidine-4-yl)-1-methylindole to obtain AZD9291. A process disclosed by the invention is simple in step, relatively high in yield, mild in reaction condition and easy for realization of industrial production.
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Paragraph 0047-0048
(2017/08/19)
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- Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
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The invention provides dimethyl sulfonate of a compound A, a crystal form of the dimethyl sulfonate, application of the dimethyl sulfonate of the compound A in preparation of a medicine for preventing and/or treating mammal diseases, and a medicinal composition containing the dimethyl sulfonate of the compound A, wherein the mammals comprise human beings, and the diseases comprise various cancers, preferably non-small cell lung cancer, particularly mutated non-small cell lung cancer.
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Paragraph 0072
(2017/08/28)
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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The invention discloses a compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, a method for preparing the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof, and an application of the compound as shown in the formula (I) or pharmaceutically acceptable salt thereof (as shown in the specification), wherein R1 to R7 are as defined in the invention.
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Paragraph 0527; 0528; 0529; 0530; 0531; 0532
(2017/09/01)
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- Preparation method for osimertinib
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The invention provides a preparation method for osimertinib. According to the invention, the raw material 3-chloropropionic acid has low toxicity and stable properties and is easily available; reaction conditions are mild; operation is simple; high-yield high-purity osimertinib can be prepared; and the method is suitable for industrial production.
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Paragraph 0030; 0031; 0035; 0036; 0040; 0041; 0045; 0046
(2018/01/17)
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- Design, synthesis, SAR discussion, in?vitro and in?vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants
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Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in?vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.
- Zhang, Haoyang,Wu, Wenkui,Feng, Chao,Liu, Zhaogang,Bai, Enhe,Wang, Xueyuan,Lei, Meng,Cheng, Hao,Feng, Huayun,Shi, Jingmiao,Wang, Jia,Zhang, Zhao,Jin, Tao,Chen, Shanshan,Hu, Shihe,Zhu, Yongqiang
-
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- Method for preparing osimertinib mesylate
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The invention discloses a method for preparing Osimertinib mesylate. The method comprises the steps that after 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline, 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with N,N,N'-trimethyl-ethylenediamine, nitro is restored after catalytic hydrogenation, then 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to coupling reaction with 3-chloropropionyl-chloride, osimertinib is obtained after elimination with sodium hydroxide, and osimertinib reacts with salt mesylate in acetone and water to obtain osimertinib mesylate, wherein a catalyst for restoring nitro by the catalytic hydrogenation is raney nickel, palladium carbon or palladium-carbon hydroxide. The method for preparing osimertinib mesylate is low in cost, high in yield, little in environmental pollution, simple and easy in production process operation and suitable for industrialized production.
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- Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same
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The invention provides a new crystal form gamma of compound A mesylate and application of the crystal form in preparation of drugs for prevention and/or treatment of mammalian diseases. Mammals include human, the diseases include various cancers, preferably non-small cell lung cancer, especially mutant non-small cell lung cancer. The invention also provides a pharmaceutical composition containing the new crystal form gamma of compound A mesylate. (formula I).
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Paragraph 0045; 0046; 0047; 0048; 0049
(2017/07/20)
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- AZD9291 intermediate and its preparation method (by machine translation)
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The invention discloses a can be used for preparing AZD9291 (I) intermediate N-[ 2 - [[ 2 - (dimethylamino) ethyl] methylamino] - 4-methoxy-5-carboxamidine] phenyl-2-acrylamide (II) and its preparation method. Its preparation comprises the steps of:in order to 2-fluoro-4-anisidine as the starting material, the amide, substituted, nitration, reaction of reduction and guanidino- N-[ 2 - [[ 2 - (dimethylamino) ethyl] methylamino] - 4-methoxy-5-carboxamidine] phenyl-2-acrylamide (II). The invention also discloses a compound of the formula II with (2E) - 3-dimethylamino-1 - (1-methyl -1H-Indol-3-yl) - 2-propen-1-one (III) preparing AZD9291 by a cyclization reaction (I) of the method. The raw materials of this preparation method is easy to obtain, process is simple, economic and environmental protection, is suitable for industrial production. (by machine translation)
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- Method for preparing mereletinib mesylate
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The invention relates to a method for preparing mereletinib mesylate. The method comprises the following steps: using N-carbobenzoxy-2-methoxy-4-fluoro-5 nitroaniline as a starting material, performing aminolysis, reduction, substitution, catalytic hydrogenation for debenzylation, and substitution reaction, and obtaining the mereletinib mesylate. The preparation method has the advantages of easiness in operation and high yield; the quality of intermediates and the quality of final products are good, and industrial production is facilitated.
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- HETEROARYL COMPOUNDS FOR KINASE INHIBITION
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Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFRand mutant HER2 activity, are described herein.
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Paragraph 526
(2016/04/26)
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- A novel and efficient synthesis of anti-cancer agent, mereletinib
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A convenient route for the synthesis of a third-generation epidermal growth factor receptor inhibitor, mereletinib (AZD9291) using starting materials that are commercially available has been achieved through reactions that are readily conducted under mild conditions. Importantly, a 5 g scale synthesis was also accomplished and this method could therefore be useful in the synthesis of similar drugs.
- Liu, Haidong,Lv, Yongfeng,Li, Yuan,Cai, Jin,Chen, Junqing,Qin, Yu,Ji, Min
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p. 318 - 320
(2015/08/18)
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- Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor
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Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
- Finlay, M. Raymond V.,Anderton, Mark,Ashton, Susan,Ballard, Peter,Bethel, Paul A.,Box, Matthew R.,Bradbury, Robert H.,Brown, Simon J.,Butterworth, Sam,Campbell, Andrew,Chorley, Christopher,Colclough, Nicola,Cross, Darren A. E.,Currie, Gordon S.,Grist, Matthew,Hassall, Lorraine,Hill, George B.,James, Daniel,James, Michael,Kemmitt, Paul,Klinowska, Teresa,Lamont, Gillian,Lamont, Scott G.,Martin, Nathaniel,McFarland, Heather L.,Mellor, Martine J.,Orme, Jonathon P.,Perkins, David,Perkins, Paula,Richmond, Graham,Smith, Peter,Ward, Richard A.,Waring, Michael J.,Whittaker, David,Wells, Stuart,Wrigley, Gail L.
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p. 8249 - 8267
(2014/12/11)
-
- 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER
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The present invention relates to certain 2-(2,4,5-substituted-anilino) pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.
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