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Preparation method of high-purity topiroxostat

A technology of topinostat and mixed solvents, which is applied in the field of preparation of topinostat, and can solve the problems of inability to obtain medicinal topinostat and difficult removal by processing technology

Inactive Publication Date: 2017-05-10
北京满格医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the compound I obtained, because it has not been purified, the HPLC purity is about 80%
Wherein the compound I contains the impurity A (structure as follows) produced by the reaction, which is converted into the corresponding impurity B in the process of continuing the synthesis of topicastat, and the subsequent treatment process is difficult to remove, and the pharmaceutical topicastat meeting the quality standard cannot be obtained.

Method used

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  • Preparation method of high-purity topiroxostat
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  • Preparation method of high-purity topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1, the preparation of compound I crude product

[0037] Repeat patent EP1650204A1.

[0038] Add 600.0mL of N,N-dimethylformamide and 60.0g of compound II to the reaction flask in sequence, under the protection of nitrogen, cool down to 10°C, then add 39.9mL of benzyl chloride methyl ether and 40.2mL of triethylamine dropwise. After dropping, the temperature of the reaction solution was raised to 85°C, stirred for 2 hours, the reaction was stopped, the temperature was lowered to 0°C, 40.1mL of trimethylsilyl cyanide was added dropwise, the dropwise addition was completed, and stirred for 30min, the system turned into an orange suspension, and the temperature was controlled for 5 Below ℃, add 55.5mL of N,N,-dimethylcarbamoyl chloride dropwise, stir at 5°C for 1 hour, raise the temperature to 35°C, and stir for 10 hours, the system is dark brown with crystals precipitated. Cool the reaction solution to 5°C, slowly add 240mL of saturated aqueous sodium bicarbona...

Embodiment 2

[0040] Embodiment 2, the purification of compound I

[0041] Add 5.0g (content: 58%) of dark brown oil (Intermediate I) into the reaction flask, add 50mL of methanol, heat up to reflux, stir to dissolve, slowly add 15mL of purified water dropwise, and drop it over in 15 minutes. Stir for 40 minutes after dropping, cool down to room temperature, filter, and rinse the filter cake with 10 mL of methanol and water (1:3) and with 10 mL of purified water. After drying at 60°C, 2.4 g of off-white solid was obtained. Product purity: 94.1%; reduced yield: 82.7%. Topirestat was prepared in this way, and the obtained topicastat HPLC detection results were as follows, purity: 99.87%; impurity B: 0.04%.

Embodiment 3

[0042] The purification of embodiment 3 compound I

[0043] Add 5.0g (content: 58%) oily substance into the reaction flask, add 50mL of isopropanol, heat up to reflux, stir to dissolve, slowly add 15mL of purified water dropwise, and finish dropping in 15 minutes. Stir for 40 minutes after dropping, cool down to room temperature, filter, and rinse the filter cake with 10 mL of isopropanol and 10 mL of purified water. The material was dried at 60°C to obtain 2.5 g of solid. Purity: 94.8%; Yield after discount: 86.2%. Topirestat was prepared in this way, and the obtained topicastat HPLC detection results were as follows, purity: 99.65%; impurity B: 0.14%.

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Abstract

The invention relates to the field of organic chemistry and pharmaceutical chemistry, specifically to a preparation method of topiroxostat. The technical scheme of the preparation method comprises a step I, dissolving a crude product (an oily product) of a compound I in an alcohol solvent or a mixed solution of an alcohol solvent and another solvent, raising the temperature to a reflux temperature, performing stirring and dissolving, slowly dropwise adding water till a few solid is precipitated, performing thermal insulation and stirring, reducing the temperature to 0 DEC C, performing stirring, carrying out cooling for crystallization, and performing filtration and drying to obtain a compound I with high purity; a step 2, adding the compound I obtained in the step I into a mixed solution of toluene and isopropanol, raising the temperature to 80 DEG C for solution, dropwise adding concentrated hydrochloric acid, performing thermal insulation and stirring, performing cooling to reach the room temperature, and performing drying at 60 DEG C to obtain topiroxostat hydrochloride; and a step 3, preparing topiroxostat. According to the preparation method of high-purity topiroxostat, concentrated hydrochloric acid instead of p-toluenesulfonic acid is used, and through purification of the intermediate compound I, the high-purity compound I is obtained, so that high-purity topiroxostat is prepared.

Description

[0001] Technical field: [0002] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of topinostat. [0003] Background technique: [0004] Topirostat, Chinese chemical name: 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole; trade name: Topiroxostat; manufactured by Fuji Pharma It was first developed by Industry Co., Ltd. for the treatment of gout and hyperuricemia. It was approved for production and sales in Japan in June 2013. Topicastat Tablets is a non-purine selective inhibitor of xanthine oxidase, which can selectively and reversibly inhibit xanthine oxidoreductase, reduce serum uric acid levels, and exhibit long-term urate-lowering effect. Topicastat tablets can effectively treat gout and hyperuricemia, and its clinical trial data have confirmed that the drug has less toxic adverse reactions, is well tolerated, is widely used, and is effective in patients with moderate to severe hepatic and renal insu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 赵乾坤卢作勇彭涛汪娟
Owner 北京满格医药科技有限公司
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