Roxadustat purification method

A purification method, the technology of Bomei, is applied in the purification field of small molecule inhibitor - Kebomei (FG-4592), achieving the effect of high yield, easy operation and simple production method

Inactive Publication Date: 2017-07-04
XUZHOU WANBANG JINQIAO PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Roxadustat purification method

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Embodiment 1

[0027] 50 g of homemade Kebomei crude product (HPLC purity 94.5%, impurity 3.8%) and 250 g of acetone were heated to 60 ºC and stirred for 12 hours. Cool at 10 ºC, filter, and collect the filter cake. Add 250 isopropanol / toluene to the filter cake, raise the temperature to 80 ºC and stir for 10 hours, cool and stir at 10 ºC, filter, and rinse the filter cake with 40 g of acetone. After vacuum drying at 45 ºC for 6 hours, 41 g of off-white solid was obtained, the HPLC purity was 99.81%, the largest single impurity amount was 0.04%, and the total impurity amount was 0.19%.

Embodiment 2

[0029] 50 g of homemade Kebomei crude product (HPLC purity 94.5%, impurity 5.5%) and 300 g of acetone were heated to 55 ºC and stirred for 8 hours. Cool at 20 ºC, filter, and collect the filter cake. Add 300g tetrahydrofuran / toluene to the filter cake, raise the temperature to 75 ºC and stir for 15 hours, cool and stir at 20 ºC, filter, and rinse the filter cake with 65 g of acetone. After vacuum drying at 45 ºC for 6 hours, 40 g of off-white solid was obtained. The HPLC purity was 99.79%, the largest single impurity amount was 0.08%, and the total impurity amount was 0.21%.

Embodiment 3

[0031] 50 g of homemade Kebomei crude product (HPLC purity 94.5%, impurity 5.5%) and 280 g of acetone were heated to 60 ºC and stirred for 12 hours. Cool at 5 ºC, filter, and collect the filter cake. Add 250 g of isopropanol / toluene to the filter cake, raise the temperature to 90 ºC and stir for 8 hours, cool and stir at 5 ºC, filter, and rinse the filter cake with 50 g of acetone. After vacuum drying at 45 ºC for 4 hours, 40 g of off-white solid was obtained. The HPLC purity was 99.75%, the largest single impurity amount was 0.06%, and the total impurity amount was 0.25%.

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Abstract

The invention discloses a method for purifying roxadustat by using a mixing solvent. The concrete process comprises: (a) dissolving a roxadustat crude product in a first solvent, carrying out heating stirring, carrying out cooling filtering at a room temperature, and collecting the filter cake; (b) adding a second mixing solvent to the collected filter cake, carrying out heating stirring, and cooling at a room temperature; and (3) filtering, washing the filter cake, and carrying out vacuum drying to obtain the pure roxadustat product. According to the present invention, the impurity removing effect of the purification method is significant, wherein the total impurity content of about 5.5% can be reduced to 0.20% and below, the purity of the purified roxadustat can be about more than 99.80%, the maximum single impurity is less than 0.1%, the yield is more than 75%, and the obtained roxadustat can meet the bulk drug level, and can meet the clinical and commercial use quality and management standards.

Description

technical field [0001] The invention belongs to the technical field of the pharmaceutical industry, and in particular relates to a purification method of a small molecule inhibitor, Kebomei (FG-4592). Background technique [0002] Kebomei (FG-4592) (Roxadustat) belongs to isoquinoline compounds, chemical name is 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide) acetic acid, molecular formula :C 19 h 16 N 2 o 5 , CAS number: 808118-40-3, the structural formula is as follows: [0003] [0004] Kebomei (FG-4592) is a small molecule inhibitor developed by American company FibroGen (FibroGen) to inhibit the activity of hypoxia-inducible factor prolyl hydroxylase. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are protein transcription factors that mimic the body's natural physiological response to hypoxia, initiating erythropoiesis (the process by which red blood cells are produced) and other protective systems. The drug has been shown to help...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 李春雷陈胜乔德水高雪芹
Owner XUZHOU WANBANG JINQIAO PHARMA
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