Method for preparing high-purity esomeprazole magnesium

A high-purity technology of esomeprazole magnesium, applied in organic chemistry methods, organic chemistry, etc., can solve problems such as unfavorable products, difficulty in mass production, and product deterioration

Active Publication Date: 2019-10-08
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] The above scheme adopts potassium methylate, which is a strong base and 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 solid becomes blocky and insoluble in toluene, even if heated to reflux. Dissolved, in mass production, these solids stick to the bottom of the reactor or form a lump, which is difficult to 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 relatively 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 has a small pore 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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  • Method for preparing high-purity esomeprazole magnesium
  • Method for preparing high-purity esomeprazole magnesium
  • Method for preparing high-purity esomeprazole magnesium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of sodium salt: Weigh 10g (55.48mmol) 2-mercapto-5-methoxybenzimidazole and add it to 100ml 5% sodium hydroxide aqueous 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] Transfer the organic phase into a 500ml three-necked flask, raise the temperature to slight reflux, add 3.8g diethyl tartrate, stir well, then add 2.6g isopropyl titanate dropwise, and stir 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, quench with water after t...

Embodiment 2

[0040] Preparation of sodium salt: Weigh 10g (55.48mmol) 2-mercapto-5-methoxybenzimidazole and add it to 100ml 5% sodium hydroxide aqueous 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 organic phase was washed with 50ml of purified water, the liquid was separated, and the organic phase was dried with 10g 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, quench with water after ...

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 and dissolve. Take 12.5g 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 take a sample for TLC. After the reaction was completed, the organic phase was washed with 50 ml of purified water, and the liquid was separated. The organic phase was dried with 10 g of anhydrous sodium sulfate and filtered.

[0045] Transfer the organic phase into a 500ml three-necked flask, raise the temperature to slight reflux, add 3.8g diethyl tartrate, stir well, then add 2.6g isopropyl titanate dropwise, and stir 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% sodium bicarbonate Quench, sep...

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Abstract

The invention relates to a method for preparing high-purity esomeprazole magnesium. The method comprises the following steps: mixing omeprazole sulfide, diethyl tartrate and titanium isopropoxide, adding diisopropylethylamine, performing stirring, dropping cumene hydroperoxide, and performing separation so as to obtain an oil substance; adding a strong base, performing stirring, adding the strongbase time by time, performing extraction and washing, performing TLC (thin-layer chromatography) monitoring, and stopping adding the strong base when trace points are generally vanished; performing cooling, crystal separation, filtration and leaching so as to obtain an esomeprazole salt; dissolving the esomeprazole salt with water, reducing the temperature to 20 DEG C or less, adjusting the pH value, dropping a magnesium sulfate heptahydrate solution, and after dropping, performing stirring, filtration, leaching and drying so as to obtain a crude product of esomeprazole; dissolving the crude product of the esomeprazole with methanol, performing decoloring with activated carbon, performing filtration, concentration and secondary dissolution, adding an acetone solution, and performing stirring, suction filtration and drying, so as to obtain the esomeprazole magnesium. The product prepared by using the method is high in purity, high in yield and small in impurity.

Description

technical field [0001] The invention belongs to the field of a medicine preparation method, in particular to a preparation method of high-purity 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 Pharmaceutical Co., Ltd., is listed in the United States under the trade name "Nexium". [0003] Esomeprazole magnesium is the magnesium salt of esomeprazole, and Astra Company expresses that sodium salt and magnesium salt are the best esomeprazole salts of effectiveness in CN1110477. Lin Qing's "Preparation, Characterization and Mutual Transformation of Esomeprazole Magnesium Polymorphs" shows that esomeprazole m...

Claims

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Application Information

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Patent Type & Authority Applications(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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