- Preparation method of osimertinib mesylate
-
The invention discloses a preparation method of osimertinib mesylate. 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole are subjected to a condensation reaction and then subjected to a nucleophilic substitution reaction with N, N-dimethylethylenediamine, a high-purity compound shown in the formula (6) is obtained through Eschweiler-Clarke amine reductive alkylation, water serves as a solvent, acetic acid and the like serve as a cosolvent, catalytic hydrogenation is performed, amidation reaction with acryloyl chloride is carried out to obtain high-purity osimertinib and salifying with methanesulfonic acid is carried out to obtain osimertinib mesylate, and compared with the patent CN103702990B, the method is simple and convenient to operate, less in environmental pollution, high in yield, low in cost, good in product quality and more suitable for industrial production.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF OSIMERTINIB MESYLATE
-
The present invention relates to an improved process for the preparation of Osimertinib mesylate with high purity and high yield.
- -
-
Paragraph 6; 7
(2021/06/11)
-
- Synthetic method of osimertinib AZD9291
-
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.
- -
-
-
- Preparation method for osimertinib mesylate
-
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.
- -
-
-
- Osimertinib preparation method
-
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.
- -
-
Paragraph 0071; 0072; 0073
(2018/10/27)
-
- Osimertinib mesylate preparation method
-
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.
- -
-
-
- Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same
-
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).
- -
-
Paragraph 0050; 0051; 0052; 0053
(2017/07/20)
-
- Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
-
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.
- -
-
Paragraph 0076
(2017/08/28)
-
- Method for preparing osimertinib mesylate
-
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.
- -
-
Paragraph 0076-0078
(2017/10/07)
-
- 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
-
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.
-
p. 8249 - 8267
(2014/12/11)
-
- 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER
-
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.
- -
-
-
