Method for synthesizing and refining esomeprazole sodium

A technology for esomeprazole sodium and meprazole potassium, applied in the field of medicine, can solve the problems of low product purity, difficult to control, influence on yield of qualified products, etc., and achieves high reaction selectivity, easy operation and high production efficiency Effect

Active Publication Date: 2014-02-12
哈药集团股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method is convenient and feasible, it is easier to generate sulfone compounds (oxidized impurities) under the action of oxygen and light during the reaction process, which is difficult to control in the industrial production process and is easy to cause The purity of the product is low, which in turn affects the yield of qualified products

Method used

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  • Method for synthesizing and refining esomeprazole sodium
  • Method for synthesizing and refining esomeprazole sodium
  • Method for synthesizing and refining esomeprazole sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1 prepares prochiral sulfide thing

[0048] Take 80.0g (2.0mol) of sodium hydroxide and add 300ml of water to dissolve it, cool down to below 40°C, and then add it to 900ml of methanol under stirring. Add 150.0g (0.83mol) of 2-mercapto-5-methoxybenzimidazole into the above solution and stir until dissolved, which takes about 30 minutes. After dissolving, 185.0 g (0.83 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride was added to the reaction liquid. Heated to 65°C and reacted for 3 hours. When the temperature of the reaction solution drops below 30°C, add 600ml of dichloromethane and 300ml of water, stir for about ten minutes to dissolve the turbidity, separate the dichloromethane layer, extract the water layer with 300ml of dichloromethane three times, and combine the dichloromethane The methane layer was washed once with 300 ml of saturated brine. Dry over anhydrous sodium sulfate and concentrate in vacuo to obtain the crude product of...

Embodiment 2

[0049] Embodiment 2 prepares the crude product of esomeprazole potassium

[0050] Add 240.0g (0.73mol) of sulfide to 1500ml of toluene, heat to 70°C under stirring to dissolve, then cool down to 47°C to 50°C, add 150.4g (0.73mol) of D-(-)-diethyl tartrate ), 103.8g (0.37mol) of tetraisopropyl titanate, 4g (0.06mol) of water, and kept at 47℃~50℃ for 2.5h. Then lower the temperature to 0℃~5℃, add 94.4g (0.73mol) of diisopropylethylamine, stir for 10min, keep 0℃~5℃ and dropwise add 196.6g (1.09mol) of cumene hydroperoxide toluene solution (mass Concentration 85%). After the dropwise addition was completed, the reaction was continued for 4.5 hours at 0°C to 5°C. Dissolve 81.8g (0.73mol) of potassium hydroxide in 800ml of methanol. After the reaction is complete, add potassium hydroxide methanol solution dropwise into the reaction solution at 0°C to 5°C, and stir for 2 hours to crystallize. Filtration, washing with a small amount of methanol, and vacuum drying yielded 243.4 g of...

Embodiment 3

[0051] Embodiment 3 prepares the crude product of esomeprazole potassium

[0052] Add 240.0g (0.73mol) of sulfide to 1500ml of toluene, heat to 70°C under stirring to dissolve, then cool down to 47°C to 50°C, add 150.4g (0.73mol) of D-(-)-diethyl tartrate ), 103.8g (0.37mol) of tetraisopropyl titanate, 4g (0.06mol) of water, and kept at 47℃~50℃ for 2.5h. Then cool down to 5°C-10°C, add 94.4g (0.73mol) of diisopropylethylamine, stir for 10min, keep 7°C-10°C and dropwise add 157.3g (0.87mol) of cumene hydroperoxide toluene solution (mass Concentration 85%). After the dropwise addition was completed, the reaction was continued at 7°C to 10°C for 5 hours. Dissolve 81.8g (0.73mol) of potassium hydroxide in 800ml of methanol. After the reaction is complete, cool down to 0°C to 5°C, add potassium hydroxide methanol solution dropwise into the reaction solution, and stir for 2 hours to crystallize. Filtration, washing with a small amount of methanol, and vacuum drying yielded 245.7 ...

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PUM

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Abstract

The invention relates to a method for synthesizing and refining esomeprazole sodium. The method comprises the following several steps: (1) carrying out condensation by taking 2-sulfydryl-5-methoxybenzimidazole and 2-chloromethyl-3.5-dimethyl-4-methoxypyridine hydrochloride as raw materials to generate prochiral thioether; (2) synthesizing the prochiral thioether into an esomeprazole crude product under the action of D-(-) diethyl tartrate, water, tetraisopropyl titanate, diisopropylethylamine and cumene hydroperoxide, and refining to generate esomeprazole potassium salt; (3) dissolving the esomeprazole potassium salt, then transforming into esomeprazole sodium salt, and refining to obtain a final product. The process of the esomeprazole sodium has the advantages of easiness for operation, good reaction repeatability and higher yield; the obtained product is high in purity and suitable for industrialized production.

Description

technical field [0001] The invention relates to a production synthesis and refining process of esomeprazole sodium, which belongs to the technical field of medicine. Background technique [0002] Chemical name of esomeprazole sodium: 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl -1H-Benzimidazole Sodium [0003] The structural formula is: [0004] [0005] Molecular formula: C 17 h 18 N 3 NaO 3 S [0006] Molecular weight: 367.41 [0007] Esomeprazole sodium is the levoisomer of omeprazole sodium, which was developed by AstraZeneca and first launched in the United States in 1999. It is the first isomer proton pump inhibitor (PPI) to be marketed. Esomeprazole sodium reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells, so it can effectively treat gastric ulcer, duodenal ulcer, functional dyspepsia and reflux esophagitis and other diseases. Compared with omeprazole sodium, esomeprazole sodium meta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 袁淑杰王丽娜杨新春张道旭王忠齐岩刘磊李郑武张珊珊高晶宋紫玉关录凡
Owner 哈药集团股份有限公司
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