Method for preparing febuxostat G crystal form

A febuxostat and crystal form technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of high solvent ratio and difficult solvent recovery, and achieve low solvent ratio, low product loss, and reproducibility of the preparation process Good results

Inactive Publication Date: 2017-02-15
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Without exception, the above patents use organic solvents that are miscible with water for crystallization. The solvent recovery in the mother liquor after crystallization is very difficult and has an inevitable negative impact on the environment. The ratio of solvent to water has certain requirements, and the ratio of solvent is relatively high. When the ratio of solvent is not controlled properly, alcohol solvate or crystal form A may be obtained. At the same time, no specific yield is mentioned in each patent

Method used

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  • Method for preparing febuxostat G crystal form
  • Method for preparing febuxostat G crystal form
  • Method for preparing febuxostat G crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 20g of febuxostat and 80ml of ethyl acetate to the reaction bottle, then add 8ml of purified water, control the temperature at 75-80°C and stir until it dissolves, then slowly cool down to 5°C, filter, dry in vacuum at 60°C, and discharge , to obtain febuxostat G crystal form 18.8g with a yield of 94.0%. result:

[0034] figure 1 It is the solubility trend diagram of water in ethyl acetate for febuxostat solubilization. It can be seen from the figure that with the increase of water in the solution system, the solubility of febuxostat increases continuously, and the solubility of febuxostat increases at high temperature. The effect is particularly obvious. However, the solubility does not change much at low temperature. Embodiment 1 utilizes this principle to obtain febuxostat with high yield.

[0035] DSC test, XRD test and FTIR test were performed on the obtained febuxostat G crystal form.

[0036] figure 2 It is the febuxostat G crystal form DSC collection o...

Embodiment 2

[0040] Add 20g of febuxostat and 60ml of isopropyl acetate to the reaction bottle, then add 9ml of purified water, control the temperature at 80-90°C and stir until it dissolves, then slowly cool down to 5°C, filter, and vacuum-dry at 70°C to produce Febuxostat G crystal form 19.2g was obtained, and the yield was 96.0%, which was determined to be Form G crystal form.

Embodiment 3

[0042] Add 20g of febuxostat and 120ml of methyl acetate to the reaction bottle, then add 12ml of purified water, control the temperature at 55-60°C and stir until it dissolves, then slowly cool down to 5°C, filter, dry in vacuum at 65°C, and discharge , 18.9 g of febuxostat G crystal form was obtained, the yield was 94.5%, and it was determined to be Form G crystal form.

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Abstract

The invention provides a method for preparing a febuxostat G crystal form. The method specifically comprises the following steps: adding febuxostat into an ester type solvent, adding water into the system, heating, performing stirring clarification, cooling to 5 DEG C below zero to 10 DEG C, filtering, and drying to obtain the febuxostat G crystal form. Compared with the prior art, the method provided by the invention has the characteristics of being low in solvent multiplying power, easy in solvent recycling, high in crystaization yield, simple in preparation method, good in repeatability and the like, commercial large-scale production can be relatively easily achieved, and very high popularization and application values can be achieved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of febuxostat crystal form G. Background technique [0002] Febuxostat, the chemical name is 2-[(3-cyano-4-isobutoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, and its chemical structure 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. The patent US6225474 of Teijin Corporation of Japan points out that febuxostat has multiple crystal forms, and this patent records the crystal forms A, B, C, D, G of the compound and the amorphous compound and its preparation method; China CN 1970547B introduces H Form I, I, J three crystal forms and preparation methods thereof; European patent EP 2399911 introduces Form I, II, tert-amyl alcohol solvate three crysta...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07B2200/13C07D277/56
Inventor 钱刚娄健龙张文灵王鹏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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