Preparation method of topiroxostat

A technology of topinostat and intermediates, which is applied in the field of preparation of pharmaceutical raw materials, can solve the problems of low yield, poor safety, and many by-products, and achieve the effects of high product purity, low production cost, and less toxic substances

Active Publication Date: 2018-01-12
HEBEI UNIV OF CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a kind of preparation method of topirestat, to solve the problem of poor safety, lower yield and many by-products in the existing topirestat synthesis process

Method used

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  • Preparation method of topiroxostat
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  • Preparation method of topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 20g of methyl 2-cyanoisonicotinate and 160ml of ethanol into a glass reaction bottle, stir and cool down to -15°C, start to add 21.6g of hydrazine hydrate dropwise while stirring, and control the temperature during the dropping process to about -15°C, about After 30 minutes of dripping, after the addition is completed, the temperature is controlled at -15°C and the reaction is stirred for 2.5 hours. After the end point of the reaction is monitored by TLC, the reaction is stopped, centrifuged, and the filter cake is collected. The filter cake is washed with 50ml of ethanol and dried. Chloromethane, add 260ml of hydrochloric acid aqueous solution with a volume concentration of 10% under stirring, stir to dissolve all the solids, separate the liquids, add 120ml of ethyl acetate to the water phase, adjust the pH to 6.5 with KOH under stirring, separate the liquids after stirring for 10 minutes, and collect For the organic phase, repeat the above extraction operation for ...

Embodiment 2

[0040] Put 100ml of absolute ethanol into a 500ml reaction bottle, add sodium sliced ​​into thin slices, stir to prepare sodium ethoxide, continue to stir for 1h after the sodium is completely reacted, add 10.8g of 4-cyanopyridine, stir at 25°C for 1h, add Acetic acid aqueous solution, adjust the pH value to 5.0, stir for 10 minutes, add 14 g of the intermediate 2-cyanoisonicotinic acid carbohydrazide prepared in Example 1, start oil bath heating and circulation, reflux at 80 ° C, reflux for 7 hours, and monitor by HPLC , when the raw material 2-cyanoisonicotinic acid carboxylhydrazide obtained by the peak area normalization method is ≤0.5%, stop heating and circulation, release the heat transfer oil in the jacket, wait until the temperature is lowered to below 30°C, discharge the material and centrifuge, The filter cake was rinsed twice with 50ml ethanol. The filter cake was transferred to an enamel baking tray and dried under reduced pressure (80°C / <-0.9MPa / 8h) to obtain 18g...

Embodiment 3

[0054] Add 20g of methyl 2-cyanoisonicotinate and 160ml of ethanol into a glass reaction bottle, stir and cool down to -15°C, start to add 14.4g of hydrazine hydrate dropwise while stirring, and control the temperature during the dropping process to about -15°C, about After 30 minutes of dripping, after the addition is completed, the temperature is controlled at -15°C and the reaction is stirred for 2.5 hours. After the end point of the reaction is monitored by TLC, the reaction is stopped, centrifuged, and the filter cake is collected. The filter cake is washed with 50ml of ethanol and dried. Chloromethane, add 260ml of hydrochloric acid aqueous solution with a volume concentration of 10% under stirring, stir to dissolve all the solids, separate the liquids, add 120ml of ethyl acetate to the water phase, adjust the pH to 6.5 with KOH under stirring, separate the liquids after stirring for 10 minutes, and collect For the organic phase, repeat the above extraction operation for ...

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Abstract

The invention provides a preparation method of topiroxostat. The preparation method comprises the steps that 2-cyano methyl isonicotinate is used as raw materials; hydrazinolysis is performed at -10 DEG C to -20 DEG C to obtain an intermediate; the intermediate and 4-cyanopyridine react under the conditions with sodium ethoxide and the pH being 4 to 6 to obtain the topiroxostat. The preparation method has the advantages that the 2-cyano methyl isonicotinate is used as a starting material; the 2-cyano methyl isonicotinate and hydrazine hydrate take condensation reaction at low temperature to prepare the intermediate; the intermediate and the 4-cyanopyridine are subjected to condensation and loop closing under the acid condition with sodium ethoxide to prepare the topiroxostat. The raw materials can be easily obtained; the reaction conditions are mild and are easy to control; a reagent with high toxicity is not used in the reaction process; the released toxic substances are few; the sidereaction products are few; the reaction safety is high; the pollution is small; the obtained purity is high; the preparation method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of medical raw material, specifically relate to a kind of preparation method of topinostat. Background technique [0002] Nowadays, the incidence of gout and hyperuricemia in our country is increasing year by year, and it has changed from a rare disease to a common disease, and more and more patients are suffering from the disease. At present, the main clinical drug is allopurinol, but to achieve the desired medicinal therapeutic effect, a large dosage is required, and the resulting drug accumulation will also cause many adverse reactions and even fatal. [0003] Topinastat was developed by Japan Fuji Pharmaceutical Co., Ltd. and was approved for marketing in Japan in 2013. Topinastat has a significant therapeutic effect on gout, and it is well tolerated and has few adverse reactions. Therefore, it is easy to develop a synthesis operation It is of great significance to synthesize the crude ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D213/86
Inventor 刘兴超徐向奎李春花张凯楚立
Owner HEBEI UNIV OF CHINESE MEDICINE
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