Method for preparing high-purity topiroxostat

A topicastat, high-purity technology, applied in the field of medicinal chemistry, can solve problems such as adverse reactions, effects of purine and pyridine metabolizing enzymes, and achieve the effects of improving purity and improving stability

Inactive Publication Date: 2017-08-25
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] At present, allopurinol is the main drug for the treatment of hyperuricemia and gout caused by hyperuricemia, but as a purine analogue, allopurinol inevitably affects purine and pyridine metabolizing enzymes
And the accumulation of its metabolites can lead to serious adverse reactions

Method used

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  • Method for preparing high-purity topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Make 37.5ml of ethanol and 37.5ml of water into a mixed solvent for later use. In a 250ml four-neck bottle, mix 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazole‐3‐yl]pyridine Dissolve 3.0g (7.16mmol) of ‐2‐nitrile p-toluenesulfonate in 30ml of mixed solvent, take a 100ml Erlenmeyer flask, dissolve 2.1ml of triethylamine in the remaining 45ml of mixed solvent, and keep the temperature at 20‐25°C , a solution of triethylamine was added to a solution of 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile p-toluenesulfonate, Immediately thereafter, 6 mol / L hydrochloric acid was dropped into the reaction system (the addition was completed within 5 minutes), and the temperature was kept below 30° C., and the stirring was continued for 6 hours. After the reaction is completed, filter, wash with 10 ml of water, and dry under reduced pressure (0.1 MPa) at 80° C. for 15 hours to obtain the finished product of topicastat. (Yield 92.6%, HPLC purity 99.6%).

[0023] Melting poi...

Embodiment 2

[0025] Make 37.5ml of ethanol and 37.5ml of water into a mixed solvent for later use. In a 250ml four-neck bottle, mix 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazole‐3‐yl]pyridine Dissolve 3.0g (7.16mmol) of ‐2‐nitrile p-toluenesulfonate in 20ml of mixed solvent, take a 100ml Erlenmeyer flask, dissolve 2.1ml of triethylamine in the remaining 55ml of mixed solvent, cool down to 15°C, triethylamine A solution of the amine was added to a solution of 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile p-toluenesulfonate, followed immediately by adding 6 mol / L hydrochloric acid was added dropwise into the reaction system (the dropwise addition was completed within 10 minutes), and the temperature was kept below 25° C., and the stirring was continued for 6 hours. After the reaction is completed, filter, wash with 10 ml of water, and dry under reduced pressure (0.1 MPa) at 80° C. for 15 hours to obtain the finished product of topicastat. (Yield 91.5%, HPLC purity 99.8%).

[00...

Embodiment 3

[0028] Make 37.5ml of ethanol and 37.5ml of water into a mixed solvent for later use. In a 250ml four-neck bottle, mix 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazole‐3‐yl]pyridine ‐2‐Nitrile p-toluenesulfonate 3.0g (7.16mmol) is dissolved in 12.5ml mixed solvent, take a 100ml Erlenmeyer flask, dissolve 1.2g sodium bicarbonate in the remaining 62.5ml mixed solvent, keep the temperature at 20‐ Add the solution of sodium bicarbonate to the solution of 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile p-toluenesulfonate at 25°C After that, 6 mol / L hydrochloric acid was dropped into the reaction system immediately (the dropwise addition was completed within 5 minutes), and the temperature was kept lower than 30° C., and the stirring was continued for 6 hours. After the reaction is completed, filter, wash with 10 ml of water, and dry under reduced pressure (0.1 MPa) at 80° C. for 15 hours to obtain the finished product of topicastat. (Yield 92.6%, HPLC purity 99.7%).

[002...

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Abstract

The invention relates to a method for preparing high-purity 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile (namely topiroxostat). According to the method, the content of hydrolytic impurities of the topiroxostat can be effectively controlled, so that the prepared topiroxostat is controllable in quality and high in stability. The method mainly comprises the following technical steps: 1) dissolving 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrilep-toluenesulfonate by using a mixed solvent, adding alkali diluted by the mixed solvent at a room temperature, and enabling the solution to be completely clarified, wherein the mixed solvent is formed by alcohol and water; 2) rapidly adding the dosed inorganic acid into the obtained solution, and gradually separating out white crystals; and 3) filtering, washing, and drying, thereby obtaining the product.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazole‐3‐yl]pyridine‐2‐nitrile p-toluenesulfonate Desalting, preparation of high-purity 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile (ie topinostat). Background technique [0002] At present, allopurinol is the main drug for treating hyperuricemia and gout caused by hyperuricemia, but as a purine analog, allopurinol inevitably affects purine and pyridine metabolizing enzymes. And the accumulation of its metabolites can lead to serious adverse reactions. Due to the significant inhibition of xanthine oxidase by 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile (i.e., topinostat) , has been increasingly used in the treatment of chronic hyperuricemia in gout in recent years. Allopurinol only inhibits reduced xanthine oxidase, while 4‐[5‐(pyridin‐4‐yl)‐1H‐1,2,4‐triazol‐3‐yl]pyridine‐2‐carbonitrile (T...

Claims

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Application Information

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IPC IPC(8): C07D401/14
Inventor 张振沛商艳梅郑忠辉张滨易晓清孟斌
Owner SHANDONG XINHUA PHARMA CO LTD
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