High-purity afatinib preparation method

Abstract

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.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a high-purity afatinib. Background technique [0002] Afatinib is a multi-target small molecule oral drug developed by Boehringer Ingelheim, Germany, which can irreversibly bind to EGFR-HER2 tyrosine kinase, inhibit its tyrosine kinase activity, and block EGFR - HER2-mediated tumor cell signal transduction, inhibits the proliferation and metastasis of tumor cells, and promotes the apoptosis of tumor cells. The drug was approved by the US FDA in July 2013, then approved by the EMA for marketing in September 2013, and approved by the PMDA for marketing in January 2014, under the trade name Gilotrif. In February 2017, CFDA approved it for the first-line treatment of patients with advanced non-small cell lung cancer and the treatment of patients with HER2-positive advanced breast cancer. [0003] Afatinib (Afatinib), the chemical name is (E)-4-dimethylamino-but-...

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Problems solved by technology

[0009] Chinese patent CN105061410A discloses that carbon tetrabromide and organophosphorus compounds are used as condensation reagents, and methylene chloride is used as solvent to obtain afatinib through one-step condensation, but the product obtained by this method has more impurities, and the purity after recrystallization with isopropanol It only reaches 95%-98%, and carbon tetrabromide and organophosphorus compounds are highly toxic, unfriendly to the environment, and are not suitable for industrial production

[0010] Chinese patent CN106045983A discloses a similar method, and the used acid chlorination solvent is methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane or methyl tert-butyl ether; used The acyl chloride reagent is thionyl chloride, isobutyl chloroformate, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfuryl chloride, acetyl chloride or chloroacetyl chloride; the solvent used for the amidation reaction is dichloromethane , dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or acetonitrile; the amidation reaction of the method reported in this patent requires additional acid-binding agents such as triethylamine and diethylamine Increased production costs, and the purity of the product obtained is poor, and additional recrystallization with isopropanol-ethanol system is required

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