Preparation method of baloxavir intermediate

Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of a baloxavir intermediate, wherein the baloxavir intermediate is 2,-(2-aminoethoxy)-1, 1-dimethoxyethane. The synthesis route of the baloxavir intermediate specifically comprises the following steps: 1) mixing an alkaline reagent and ethanolamine to obtain a mixed solution, and heating; 2) adding chloroacetaldehyde dimethyl acetal into the mixed solution, stirring, and reacting; and 3) after the reaction is finished, adding ice water and dichloromethane for post-treatment, concentrating an organic phase, and rectifying to obtain the 2,-(2-aminoethoxy)-1, 1-dimethoxyethane. The method is high in product purity, low in cost, simple to operate, mild in condition and suitable for industrial popularization.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a method for preparing a baloxavir intermediate. Background technique [0002] Baloxavir is a new drug against influenza A and B viruses discovered by Shionogi Co in Japan and jointly developed by it and Roche. Baloxavir, a novel cap-dependent endonuclease inhibitor, was approved by the U.S. Food and Drug Administration (FDA) on October 24, 2018, for the treatment of children 12 years of age and older with flu symptoms of prolonged duration. Acute uncomplicated influenza patients over 48 hours. It is also one of the few new drugs in the world that can inhibit the proliferation of influenza virus. Because it has no effect on host cells and has few side effects, it is expected to replace oseltamivir and become the ace drug in the field of influenza. [0003] Baloxavir Marvoxil was first seen in PCT patent WO20161752224, and its structural formula is as fol...

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Problems solved by technology

[0010] (1) Compound C has good water solubility, and water needs to be added for treatment, and the organic solvent used in the reaction system is tetrahydrofuran, so what is obtained is a tetrahydrofuran solution of compound C, and it is difficult to separate the pure product;

[0011] (2) Due to the inability to separate compound C, the purity of compound D is low;

[0012] (3) Due to the inability to separate compound C, the conversion rate of compound E is low, and it is in the form of black mud, resulting in difficulty in crystallization

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