Preparation method of topiroxostat

A technology of topicastat and compounds, applied in the direction of organic chemistry and the like, can solve the problems of high cost of raw materials, harsh reaction conditions, long process routes, etc., and achieves the effects of high reaction yield, mild reaction, economical and environmentally friendly yield

Pending Publication Date: 2021-11-19
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] In order to solve the problems of using highly toxic cyanide reagents, harsh reaction conditions, long process route, high cost of raw materials and low yield in the preparation process of topinastat in the prior art, the inventio

Method used

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  • Preparation method of topiroxostat

Examples

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preparation example Construction

[0051] Preparation of Compound IV

[0052]Into a 5L three-neck flask, add 2-cyanopyridine (104.11g, 1.0mol) and 1000mL toluene at room temperature, stir and dissolve, then add concentrated sulfuric acid (39.23g, 0.4mol) dropwise, after dropping, heat up to 70℃~75℃ , add formamide aqueous solution (225.20g, 5.0mol) quickly, after dropping, start to add ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropping, keep warm at 70-75°C, TLC monitors the reaction solution Add 1000mL of purified water to the mixture, cool to room temperature and crystallize for 2 hours, filter, wash the filter cake with purified water until neutral, then wash with 200mL of ethanol, and dry in vacuum for 12 hours to prepare 2-cyano-4-carbamoyl-pyridine , yield 98.7%, HPLC purity 99.88%.

Embodiment 2

[0054] Into a 5L three-neck flask, add 2-cyanopyridine (104.11g, 1.0mol) and 1000mL toluene at room temperature, stir and dissolve, then add concentrated sulfuric acid (39.23g, 0.4mol) dropwise, after dropping, heat up to 70℃~75℃ , add formamide aqueous solution (180.16g, 4.0mol) quickly, after dropping, start to add ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropping, keep warm at 70-75°C for reaction, TLC monitors the reaction solution Add 1000mL of purified water to the mixture, cool to room temperature and crystallize for 2 hours, filter, wash the filter cake with purified water until neutral, then wash with 200mL of ethanol, and dry in vacuum for 12 hours to prepare 2-cyano-4-carbamoyl-pyridine , yield 94.2%, HPLC purity 99.79%.

Embodiment 3

[0056] Into a 5L three-necked flask, add 2-cyanopyridine (104.11g, 1.0mol) and 1000mL 1,2-dichloroethane at room temperature, stir and dissolve, then add hydrochloric acid (14.60g, 0.4mol) dropwise, dropwise, and heat up to 70 ℃ ~ 75 ℃, quickly add formamide aqueous solution (270.24g, 6.0mol), after dropping, start adding saturated aqueous solution of ammonium persulfate (342.30g, 1.5mol), after dropping, keep warm at 70 ~ 75 ℃, TLC After monitoring the completion of the reaction, add 1000 mL of purified water to the reaction liquid, cool to room temperature and crystallize for 2 hours, filter, wash the filter cake with purified water until neutral, then wash with 200 mL of ethanol, and dry in vacuum for 12 hours to prepare 2-cyano-4- Carbamoyl-pyridine, yield 93.6%, HPLC purity 99.75%.

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of topiroxostat. The preparation method disclosed by the invention comprises the following steps: 2-cyanopyridine and formamide are taken as raw materials to react to prepare 2-cyano-4-carbamoyl-pyridine; the 2-cyano-4-carbamoyl-pyridine continues to react with isoniazide to obtain a key intermediate 4-picolinic acid hydrazide-N'-(2-cyanopyridine-4-carbodiimide), and the key intermediate 4-picolinic acid hydrazide-N'-(2-cyanopyridine-4-carbodiimide) is subjected to ring closing to obtain the topiroxostat. The invention provides the novel method for synthesizing topiroxostat, which avoids the use of highly toxic chemical reagents, replaces a traditional catalyst with a green catalyst, is milder in reaction, is economical and environment-friendly, is higher in yield, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of topinostat. Background technique [0002] Topiroxostat is a new generation of highly selective and reversible xanthine oxidase inhibitor jointly developed by Fuji Pharmaceutical Co., Ltd. and Sanwa Chemical Co., Ltd., which was approved for marketing in Japan in June 2013. Compared with the current Compared with the anti-gout drugs in clinical application, there are two advantages: most of them only inhibit the reduced xanthine oxidase, while topicastat has a significant inhibitory effect on both the oxidized and reduced xanthine oxidase Therefore, its effect of lowering uric acid is more powerful and lasting; other purine analogues inevitably cause the influence of other enzyme activities involved in purine and pyridine metabolism. This product has the advantages of strong uric acid-lowering effect, less adverse reactions, and go...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D213/86
CPCC07D401/14C07D213/86
Inventor 徐杰翟立海梁茂征谢印杰刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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