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Purification method of baloxavir marboxil and derivatives thereof

A purification method and derivative technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of unfavorable preparation processing and ensure the uniformity of drug quality, easy condensation into small balls, and small particle size of the product, achieving significant cost-effectiveness , No electrostatic adsorption phenomenon, reduce the effect of solvent residue

Active Publication Date: 2021-03-26
BEIJING AOHE DRUG RES INST +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is cumbersome to operate, not suitable for industrialized large-scale production, and the obtained product has small particle size, strong adhesion, strong static electricity, easy to condense into small balls, poor fluidity and other defects, which is not conducive to preparation processing and quality uniformity of drugs.

Method used

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  • Purification method of baloxavir marboxil and derivatives thereof
  • Purification method of baloxavir marboxil and derivatives thereof
  • Purification method of baloxavir marboxil and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0045] Embodiment 1-3 Purification method of baloxavir maple ester of the present invention

[0046] The purification parameters of Examples 1-3 are shown in Table 1.

[0047] The purification method of Example 1-3 comprises the following steps: add about 65g of baloxavir maplexate crude product to the 2L three-empty bottle, add the purification solvent, stir, heat up, and reflux to dissolve; naturally cool down to the required temperature, keep warm, Stand for crystallization for about 2 hours; filter with suction, rinse the filter cake with 100mL*2 times of purified water; dry in vacuum at 40°C for 15 hours to obtain purified products 1-3. The results are shown in Table 1.

[0048] Table 1

[0049]

[0050]

Embodiment 4

[0051] Embodiment 4 Purification method of baloxavir mapobate of the present invention

[0052] Add 65g of crude baloxavir maple ester to a 2L three-neck flask, add 1755mL of methanol, stir, raise the temperature to 65°C until it is completely dissolved, cool down to 0-5°C, keep warm and crystallize for 2 hours; filter, and use purified water for the filter cake 100mL*2 washes, and the filter cake was vacuum-dried at 40°C for 15 hours to obtain an off-white solid baloxavir maplelate. HPLC purity 99.9%.

Embodiment 5

[0056] The particle size distribution of the purified baloxavir maplelate prepared in Example 4 and Comparative Example 2 was detected by the following method.

[0057] Measuring instrument: Mastersizer 3000, main parameters: wet method, stirring speed 1000rpm, ultrasonic time 4min, shading degree 5%-20%, particle refractive index 1.52%. The results are shown in Table 2 and Figure 5-Figure 6 .

[0058] Table 2

[0059]

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Abstract

The invention relates to a purification method of baloxavir marboxil and derivatives thereof, which comprises the following steps of: adding a low-molecular alcohol solvent into baloxavir marboxil andderivatives thereof, heating for dissolution, and carrying out crystallizing, filtering, and drying to obtain a purified product. The purified product obtained by the method has the advantages of high purity, proper particle size distribution and no electrostatic adsorption phenomenon, and is beneficial to improving the quality and quality uniformity of medicines and preparations thereof, and beneficial to preparation processing.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a purification method of baloxavir maplelate and derivatives thereof. Background technique [0002] WHO statistics show that the number of cases of influenza infection in the world is about 3 million to 5 million every year, and about 250,000 to 500,000 influenza infection patients die as a result. Baloxavir Marboxil is a Cap-endonuclease inhibitor used in the treatment of influenza. The drug was launched in Japan on February 23, 2018. CN107709321A BaloxavirMarboxil and its active structure baloxavir. [0003] [0004] WO2018030463A1 discloses a method for purifying baloxavir maplelate. In this method, a mixture of dimethyl sulfoxide (DMSO) and water of different concentrations is added dropwise twice to carry out elution and crystallization. This method is cumbersome to operate, not suitable for industrialized large-scale production, and the obtained product has s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/14
CPCC07D498/14C07B2200/13
Inventor 赵寅堡高院院袁景洋范建国甄志彬邓声菊徐艳君王田园
Owner BEIJING AOHE DRUG RES INST
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