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Preparation process and method for topiroxostat

A technology for the preparation of topinostat, which is applied in the field of preparation technology for topinostat, can solve problems such as unfavorable control of the quality of raw materials, high impurity content, and high toxicity of cyanide reagents, and achieve the goal of cyanohydrolysis The effect of increasing risk, improving product quality, and ensuring product quality

Inactive Publication Date: 2016-02-03
大道隆达(北京)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reflux reaction time of this process is long and the impurity content is high, which is not conducive to the quality control of raw materials
Disadvantages of this reaction: 1) the temperature is too high, and the cyano group of the alkaline system 2-cyanoisonicotinic acid hydrazide is unstable; 2) the condensation product is directly subjected to the cyclization reaction without separation, and the risk of hydrolysis of the cyano group is high, which is not conducive to Industrial production of products
p-Benzenesulfonic acid and its esters are genotoxic impurities, which are not conducive to impurity control
In addition, the cyanide reagent is highly toxic and the cost of dimethylcarbamoyl chloride is high, so it is not suitable for industrial production

Method used

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  • Preparation process and method for topiroxostat
  • Preparation process and method for topiroxostat
  • Preparation process and method for topiroxostat

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preparation example Construction

[0050] The invention discloses a preparation method of topicastat. Those skilled in the art can refer to the content of this article and make appropriate improvements to the process parameters. In particular, it should be pointed out that all similar replacements and modifications will be obvious to those skilled in the art, and they will all be deemed to be included within the scope of the present invention. The method and application of the present invention have been described through preferred embodiments, and it is obvious that relevant personnel can make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention. And apply the technology of the present invention.

[0051] Topinostat and [formula (IV), 4-pyridinecarbohydrazide-N'-(2-cyanopyridine-4-carbonimido)] detection method is the same, specifically as follows: chromatographic column is octadecyl Silane-...

Embodiment 1

[0055] Add 2.0L of methanol and 190g of 4-cyanopyridine into the reaction kettle, stir and dissolve at room temperature, add 5g of sodium methoxide, stir and react at a temperature of 20-30°C for 0.5 hours, cool down to 0-10°C and stir for 1 hour.

[0056] Add 280g of 2-cyanoisonicotinic acid hydrazide to the above reaction solution, keep warm at 0-10°C and stir for 4 hours. After the reaction is completed, filter and collect the filter cake, wash the filter cake with water, collect the filter cake, and dry the filter cake to obtain [Formula (IV), 4-pyridinecarbohydrazide-N'-(2-cyanopyridine-4-carbonimido)], weight 413g, yield 90%, off-white solid. 99.8% pure. Mass spectrum (ESI): 267.1 (M+1, molecular ion peak).

Embodiment 2

[0058] Add 2.0L of methanol and 190g of 4-cyanopyridine into the reaction kettle, stir and dissolve at room temperature, add 4g of sodium hydroxide, control the temperature at 30-40°C and stir for 0.5 hours, then cool down to 0-10°C and stir for 1 hour.

[0059] Add 280g of 2-cyanoisonicotinic acid hydrazide to the above reaction solution, keep it warm at 0-10°C and stir for 4 hours. After the reaction is complete, filter and collect the filter cake, wash the filter cake with phosphoric acid solution, collect the filter cake, and dry the filter cake to obtain [Formula (IV), 4-pyridinecarbohydrazide-N'-(2-cyanopyridine-4-carbonimido)], weight 391g, yield 85%, white solid. 99.7% purity.

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Abstract

The invention relates to a preparation process and method for topiroxostat. 4-cyanopyridine [formula (II)] and 2-cyanoisonicotinohydrazide [formula (III)] are subjected to a condensation reaction by stages to prepare [formula (IV), 4-pyridylcarbonylhydrazine-Nminute-(2-cyanopyridine-4- carbimide], washing the [formula (IV)] and then carrying out a cyclization reaction to prepare the topiroxostat [(formula (I)]. The preparation process disclosed by the invention is simple and convenient, free of special toxic reagent, green and environment-friendly, good in product yield, good in quality and in conformity with the medicinal requirement.

Description

technical field [0001] The invention relates to the technical field of pharmacy, and describes a preparation process and method of topicastat, which is widely used in the treatment of diseases such as gout and hyperuricemia. Background technique [0002] Topiroxostat (topiroxostat), developed by Fuji Pharmaceutical Co., Ltd., is a new type of highly selective and reversible xanthine oxidase inhibitor. It was approved for marketing in Japan in June 2013. Topicastat has a significant inhibitory effect on both oxidized and reduced xanthine oxidase, so its effect of lowering uric acid is more powerful and lasting, so this product can be used to treat chronic hyperuricemia in gout. Compared with allopurinol, it has two advantages: 1. Allopurinol can only inhibit xanthine oxidase in reduced form, while topicastat can significantly inhibit xanthine oxidase in both oxidized and reduced forms Therefore, its effect of lowering uric acid is more powerful and lasting; 2. Since allopur...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D213/86
CPCC07D401/14C07D213/86
Inventor 孟令桥石创业周华明朱琳田玉涛
Owner 大道隆达(北京)医药科技发展有限公司
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