Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide

A chloropyridine and pyrazine technology, applied in the field of medicine, can solve the problems of high price, high production cost, few manufacturers, etc., and achieve the effects of short reaction time, avoiding column purification and simple operation

Pending Publication Date: 2022-07-01
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The current domestic existing zopiclone impurity compound J has few manufacturers, high production cost, and high price, and the product has only 95% purity, so there is an urgent need for higher synthetic purity (more than 99%), easy operation, and easy reaction. Zopiclone impurity compound J with short time and low cost provides impurity reference substance for zopiclone consistency evaluation and daily production, and successfully completes R&D and production tasks

Method used

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  • Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide
  • Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide
  • Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide

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Experimental program
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Effect test

Embodiment 1

[0052] Pyrazine-2-carboxylic acid (12.4 g) was dissolved in dichloromethane (70 mL), and cooled to an inner temperature of 5°C in an ice-water bath. To the mixture, thionyl chloride (18 g) was added dropwise, 2-amino-5-chloropyridine (14.1 g) was added after the dropwise addition, and the mixture was stirred for 2 hours after returning to room temperature. The reaction solution was poured into water (100 mL), stirred and separated. The aqueous phase was extracted with dichloromethane (30 mL*2), the organic phases were combined, washed 3 times with saturated aqueous sodium bicarbonate solution (500 mL*3), dried over anhydrous sodium sulfate (10 g), filtered to remove the desiccant, spin-dried, Off-white solid 24.2g. To the solid, n-hexane (100 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred under reflux for 1 hour. After cooling to 0° C., the product was filtered to obtain 22.0 g of an off-white solid with a yield of 94.0% and a purity of 99.3%.

Embodiment 2

[0054] Pyrazine-2-carboxylic acid (12.4 g) was dissolved in dichloromethane (65 mL) and cooled to an inner temperature of 5°C in an ice-water bath. To the mixture, thionyl chloride (14.3 g) was added dropwise, 2-amino-5-chloropyridine (15.4 g) was added after the dropwise addition, and the mixture was stirred for 2 hours after returning to room temperature. The reaction solution was poured into water (100 mL), stirred and separated. The aqueous phase was extracted with dichloromethane (30 mL*2), the organic phases were combined, washed three times with saturated aqueous sodium bicarbonate solution (500 mL*3), dried over anhydrous sodium sulfate (10 g), filtered to remove the desiccant, spin-dried, Off-white solid 24.9g. To the solid, n-hexane (100 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred under reflux for 1 hour. After cooling to 0° C., the product was filtered to obtain 21.2 g of an off-white solid with a yield of 90.6% and a purity of 99.1%.

Embodiment 3

[0056] Pyrazine-2-carboxylic acid (12.4 g) was dissolved in dichloromethane (70 mL) and cooled to an inner temperature of 5°C in an ice-water bath. To the mixture, thionyl chloride (14.3 g) was added dropwise, 2-amino-5-chloropyridine (14.1 g) was added after the dropwise addition, and the mixture was stirred for 2 hours after returning to room temperature. The reaction solution was poured into water (100 mL), stirred and separated. The aqueous phase was extracted with dichloromethane (30 mL*2), the organic phases were combined, washed three times with saturated aqueous sodium bicarbonate solution (500 mL*3), dried over anhydrous sodium sulfate (10 g), filtered to remove the desiccant, spin-dried, Off-white solid 24.3 g. To the solid, n-hexane (100 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred under reflux for 1 hour. After cooling to 0° C., the product was filtered to obtain 22.3 g of an off-white solid with a yield of 95.3% and a purity of 99.5%.

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Abstract

The invention discloses a synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide, and the method comprises the following steps: 1) pyrazine-2-formic acid and 2-amino-5-chloropyridine are subjected to a reaction in a solvent; 2) separating reaction products; 3) purifying; wherein the solvent in the step 1) is selected from alkyl halide and thionyl chloride. The alkyl halide is selected from any one or a combination of dichloromethane, trichloromethane, 1, 1-dichloroethane and 1, 2-dichloroethane.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide. Background technique [0002] Zopiclone is a third-generation sedative-hypnotic drug developed by the French company Rhono-Poulene Rorer for the treatment of sleep disorders. Eszopiclone (Eszopiclone) is a fast-acting, short-acting non-benzodiazepine sedative and hypnotic drug developed by Seprator Company in the United States. It was launched in the United States in April 2005. Its racemate zopiclone has been listed in nearly 100 countries and regions, and eszopiclone is the first drug that can be used for long-term difficulty in falling asleep and maintain quality. Compared with its racemate, eszopiclone has medicinal properties. It has the advantages of fast effect, small side effects and low toxicity. [0003] The zopiclone structure is as follows: [0004] [0005] Its synthes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D487/04G01N30/02G01N30/06
CPCC07D401/12C07D487/04G01N30/02G01N30/06
Inventor 李睿徐学宇丁爱忠孔凯丽吴庆丽
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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