The preparation method of Febuxostat A crystal form

A technology of febuxostat and crystal form, which is applied in the field of medicinal chemistry, can solve the problems of inability to achieve reproducibility, failure to mention the yield and purity of crystal form A, etc., and achieve the effect of easy implementation, high purity and simple process

Active Publication Date: 2011-12-07
SHANDONG QIDU PHARMA
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Problems solved by technology

In the patent CN1275126, it is introduced that the method of preparing crystal A is to crystallize in a certain proportion of methanol aqueous solution, and a certain amount of aqueous solution of A seed crystal needs to be added dropwise to induce the precipitation of crystals, and this method is not mentioned in this patent. The yield and purity of the crystal form A of febuxostat, the inventors could not achieve a certain reproducibility in the preparation process according to this patent, and considering the impact of methanol on the environment, so the crystal form A of febuxostat preparation for further study

Method used

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  • The preparation method of Febuxostat A crystal form
  • The preparation method of Febuxostat A crystal form
  • The preparation method of Febuxostat A crystal form

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Put 50g of febuxostat in a 1L three-necked bottle, add 500ml of acetone, heat and reflux in a water bath for 10 minutes, after cooling, place the reaction solution in a constant temperature water bath at 25±2°C, and when crystals start to precipitate, Stirring was continued for 20 minutes at a stirring speed of 600±20 rpm, and then the reaction solution was frozen and crystallized at -10±2°C for 8 hours. Suction. The filter cake was dried under vacuum at 60±2°C and -0.08~-0.10MPa for 6 hours to obtain 47.7g of crystals. Infrared detection, see figure 1 , at 1678cm -1 、1273cm -1 There are characteristic peaks, X-diffraction measurement results see figure 2 , the reflection angle 2θ of the X-ray powder diffraction pattern of the prepared A crystal is 6.64°, 7.22°, 12.86°, 13.33°, 16.54°, 19.63°, 21.99°, 22.74°, 25.91°, 26.76°, 29.22° and have characteristic peaks at 36.74°. Confirmed as febuxostat in A crystal form. The yield was 95.4%, and the purity was 99.98%. ...

Embodiment 2

[0029] Put 50g of febuxostat in a 1L three-necked bottle, add 250ml of 95% ethanol, heat and reflux in a water bath for 10 minutes, after cooling, put the reaction solution in a water bath at 30±2°C and let it stand, when crystals begin to precipitate Afterwards, continue to stir for 25 minutes at a stirring speed of 600±20 rpm, and then freeze and crystallize the reaction solution at -12±2°C for 9 hours. Suction. The filter cake was dried under vacuum at 60±2°C and -0.08~-0.10MPa for 7 hours to obtain 47.3g of crystals. Infrared detection, see image 3 , at 1678cm -1 、1274cm -1 There are characteristic peaks, X-diffraction measurement results see Figure 4 , the reflection angle 2θ of the X-ray powder diffraction pattern of the prepared A crystal is 6.63°, 7.22°, 12.84°, 13.31°, 16.54°, 19.62°, 22.00°, 22.74°, 25.92°, 26.74°, 29.22° and have characteristic peaks at 36.75°. Confirmed as febuxostat in A crystal form. The yield was 94.6%, and the purity was 99.96%.

Embodiment 3

[0031] Put 50g of febuxostat in a 1L three-necked bottle, add 750ml of methyl ethyl ketone, heat and reflux in a water bath for 10 minutes, and after cooling, place the reaction solution in a water bath at 35±2°C to stand still. When crystals start to precipitate, Stirring was continued for 30 min at a stirring speed of 600±20 rpm, and then the reaction solution was frozen and crystallized at -8±2°C for 10 hours. Suction. The filter cake was dried under vacuum at 60±2°C and -0.08~-0.10MPa for 8 hours to obtain 46.4g of crystals. Infrared detection, see Figure 5 , at 1678cm -1 、1273cm -1 There are characteristic peaks, X-diffraction measurement results see Figure 6 , the reflection angle 2θ of the X-ray powder diffraction pattern of the prepared A crystal is 6.62°, 7.20°, 12.83°, 13.30°, 16.52°, 19.60°, 21.96°, 22.71°, 25.90°, 26.73°, 29.19° and have characteristic peaks at 36.73°. Confirmed as febuxostat in A crystal form. The yield was 92.8%, and the purity was 99.92...

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Abstract

The invention belongs to the field of medicine chemistry and particularly relates to a method for preparing Febuxostat crystal A. The method comprises: dissolving, crystallizing and drying, wherein the dissolving is to dissolve Febuxostat in a solvent with heating in a water bath, the solvent may be RCOCH3 or RCH2OH, R may be methyl or ethyl, the mass / volume ratio of the Febuxostat to the solventranges from 1:5 to 1:20, the Febuxostat is based on gram and the volume of the solvent is based on milliliter; after dissolution, placing the solution in a water bath at 25 to 40 DEG C, standing, stirring for 20 to 40 minutes upon the precipitation of crystals; placing at -15 to 0 DEG C to continue to precipitate crystals for 8 to 10 hours, and filtering; and after filtering, drying at 65 DEG C under vacuum for 6 to 8 hours to obtain the Febuxostat crystal A. The Febuxostat crystal A prepared by the invention is high in purity and yield, the process is simple and easy to implement, the yield is 92.0 to 98.0 percent and the purity is more than 99.90 percent.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of febuxostat A crystal form. Background technique [0002] Febuxostat, its chemical name is 2-[(3-cyano-4-isobutoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, its chemical structural formula is: [0003] [0004] Febuxostat was approved for marketing by EMEA in the European Union in April 2004, and was approved for marketing by FDA in the United States in February 2009. It is used for the long-term treatment of hyperuricemia with gout symptoms. Febuxostat has a variety of crystal forms, and Chinese patent CN1275126 records a compound and its preparation method involving five crystal forms of this compound, A, B, C, D, G and amorphous, invented by Teijin Corporation of Japan; 200910118404.X introduced three crystal forms H, I, J and their preparation methods. In recent years, more febuxostat crystal forms have been introduced, among which ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 郑家晴刘淑桂张建礼崔美兰李洁李后涛周海洋牛海岗
Owner SHANDONG QIDU PHARMA
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