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A kind of preparation method of esomeprazole magnesium

A technology of esomeprazole magnesium and azole thioether, which is applied in the field of pharmaceutical preparation and can solve problems such as inconvenient operation, being caught in it, and difficult to remove impurities

Active Publication Date: 2022-05-03
湖南协创药品开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Said scheme adopts potassium methylate, potassium methylate is a strong base, reacts with water to generate potassium hydroxide and methanol, it is still difficult to avoid the generation of hydroxide ions, and the concentrated potassium salt solids become lumps, insoluble in toluene, even if heated to reflux. During mass production, these solids stick to the bottom of the reactor or form a lump, which is difficult to stir and disperse, and the operation is extremely inconvenient. In addition, impurities are also trapped in it, and it is difficult to achieve a better effect through acetone reflux. Impurity removal effect
In addition, the temperature of the acetone reflux process is high, which is extremely unfavorable to the product. If it is higher than 40°C, our product will easily deteriorate and produce various impurities.
The above scheme needs to be refined to filter out the residual inorganic magnesium salt in the product. Since the particle size of the insoluble matter to be filtered out is extremely small, the filter screen used is small in size. When the output is slightly enlarged, the filter will be blocked and it is difficult to batch Production

Method used

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  • A kind of preparation method of esomeprazole magnesium
  • A kind of preparation method of esomeprazole magnesium
  • A kind of preparation method of esomeprazole magnesium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of sodium salt: Weigh 10 g (55.48 mmol) of 2-mercapto-5-methoxybenzimidazole into 100 ml of 5% aqueous sodium hydroxide solution, stir to dissolve. Take 12.5g (56.28mmol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and dissolve it in 120ml of dichloromethane, add it dropwise, heat up to reflux, keep at reflux for 1 hour, Sample TLC. After the reaction was completed, the liquid was separated, the organic phase was washed with 50 ml of purified water, the liquid was separated, the organic phase was dried with 10 g of anhydrous sodium sulfate, and filtered.

[0037] The organic phase was transferred into a 500ml three-necked flask, heated to slight reflux, and then 3.8g of diethyl tartrate was added, stirred well, then 2.6g of isopropyl titanate was added dropwise, and stirred for 0.5h. Cool down to 10±2°C, add 1.2g of N,N`-diisopropylethylamine, stir to dissolve, add dropwise 4.8g of cumene hydroperoxide, react for 2 hours, sample for TLC, ...

Embodiment 2

[0040] Preparation of sodium salt: Weigh 10 g (55.48 mmol) of 2-mercapto-5-methoxybenzimidazole into 100 ml of 5% aqueous sodium hydroxide solution, stir to dissolve. Take 12.5g (56.28mmol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and dissolve it in 120ml of toluene, add dropwise, heat up to reflux, keep at reflux for 1 hour, and sample for TLC . After the reaction was completed, the liquid was separated, the organic phase was washed with 50 ml of purified water, the liquid was separated, the organic phase was dried with 10 g of anhydrous sodium sulfate, and filtered. The organic phase was transferred into a 500ml three-necked flask, and after the temperature was raised to 55°C, 3.8g of diethyl tartrate was added, stirred well, then 2.6g of isopropyl titanate was added dropwise, and stirred for 0.5h. Cool down to 10±2°C, add 1.2g of N,N`-diisopropylethylamine, stir to dissolve, add dropwise 4.8g of cumene hydroperoxide, react for 2 hours, sample for TLC,...

Embodiment 3

[0044] Preparation of sodium salt: Weigh 10g of 2-mercapto-5-methoxybenzimidazole and add it to 100ml of 5% potassium hydroxide aqueous solution, stir to dissolve. Dissolve 12.5 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride in 120 ml of toluene, add dropwise, heat up to reflux, keep at reflux for 1 hour, and sample for TLC. After the reaction was completed, the liquid was separated, the organic phase was washed with 50 ml of purified water, the liquid was separated, the organic phase was dried with 10 g of anhydrous sodium sulfate, and filtered.

[0045] The organic phase was transferred into a 500ml three-necked flask, heated to slight reflux, and then 3.8g of diethyl tartrate was added, stirred well, then 2.6g of isopropyl titanate was added dropwise, and stirred for 0.5h. Cool down to 10±2°C, add 1.2g of N,N`-diisopropylethylamine, stir to dissolve, add dropwise 4.8g of cumene hydroperoxide, react for 2 hours, sample for TLC, finish the reaction with 5% s...

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Abstract

The invention relates to a preparation method of esomeprazole magnesium, comprising the following steps: mixing omeprazole sulfide, diethyl tartrate and isopropyl titanate, adding diisopropylethylamine, stirring, Add cumene hydroperoxide dropwise, separate to obtain an oily substance; add strong base, stir, then add strong base one by one, extract, wash, do TLC monitoring, stop adding strong base when there is basically no spot; cool down, crystallize, Filter and rinse to obtain esomeprazole salt; dissolve esomeprazole salt in water, cool down to below 20°C, adjust pH, add magnesium sulfate heptahydrate aqueous solution dropwise, after the dropwise addition, stir and filter , rinse, and dry to obtain crude esomeprazole magnesium; dissolve the crude esomeprazole magnesium with methanol, decolorize activated carbon, filter, concentrate, dissolve again, add acetone aqueous solution, stir, suction filter, dry, The esomeprazole magnesium is obtained, and the product prepared by the invention has high purity, good yield and less impurities.

Description

technical field [0001] The invention belongs to the field of medicine preparation methods, in particular to a preparation method of esomeprazole magnesium. Background technique [0002] Esomeprazole is a proton pump inhibitor that reduces gastric acid secretion and prevents the formation of gastric acid by inhibiting the H+ / K+-ATPase of gastric parietal cells. It is used for gastroesophageal reflux disease (GORD) including erosive reflux The initial and long-term treatment of liquid esophagitis (including erosive esophagitis), developed by AstraZeneca Pharmaceuticals Co., Ltd., is listed in the United States under the trade name "Nexium". [0003] Esomeprazole magnesium is the magnesium salt of esomeprazole, and Astra Corporation indicated in CN1110477 that sodium salt and magnesium salt are the best esomeprazole salts of efficacy. Lin Qing's "Preparation, Characterization and Mutual Transformation of Esomeprazole Magnesium Polymorphs" shows that esomeprazole magnesium trih...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 吴健民司敏李三新颜磊黄龙
Owner 湖南协创药品开发有限公司
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