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Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases

A technology for azole magnesium trihydrate and digestive system diseases, which is applied in the field of drug synthesis and achieves the effects of high reaction efficiency, simple and easy method, and good selectivity.

Inactive Publication Date: 2016-03-23
QINGDAO CENT HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The object of the present invention is to overcome the defect of the preparation method of existing esomeprazole, provide a kind of yield high, selectivity is good and the preparation of esomeprazole magnesium trihydrate suitable for industrial scale production is high in reaction efficiency method

Method used

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  • Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases
  • Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases

Examples

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Effect test

Embodiment 1

[0029] A preparation method of esomeprazole magnesium trihydrate, comprising the following steps:

[0030]1) In the presence of sodium hydroxide, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-mercapto-5-methoxybenzimidazole 432g in 4LTHF Reflux reaction for 3 hours to obtain omeprazole sulfide, and then refine it. The refining process is: first dissolve omeprazole sulfide in 1.5L acetonitrile at 60°C, then drop into 3L petroleum ether, and dissolve it at 0.1°C Cool down to 10°C at a speed of 1 / s, let it stand for 1 hour, centrifuge and filter to obtain 650g of refined omeprazole sulfide, the yield is 85.9%, and the purity is 99.81%. 2-Chloromethyl-3,5-di The molar ratio of methyl-4-methoxypyridine hydrochloride to 2-mercapto-5-methoxybenzimidazole and sodium hydroxide is 1:0.8:0.1;

[0031] 2) Mix 630 g of omeprazole sulfide obtained in step 1) with the compound represented by formula A and the inorganic metal salt in 5 L of acetone. The mixing condit...

Embodiment 2

[0035] A preparation method of esomeprazole magnesium trihydrate, comprising the following steps:

[0036] 1) In the presence of potassium hydroxide, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-mercapto-5-methoxybenzimidazole 649g in 4LTHF reflux reaction for 4 hours to obtain omeprazole sulfide, and then refine it. The refining process is as follows: first dissolve omeprazole sulfide in 1.5L acetonitrile at 65°C, then drop 3.5L petroleum ether into 0.1 Cool down to 15°C at the speed of ℃ / s, let it stand for 1 hour, centrifuge and filter to obtain 845g of refined omeprazole sulfide, the yield is 89.1%, and the purity is 99.79%. Among them, 2-chloromethyl-3, The molar ratio of 5-dimethyl-4-methoxypyridine hydrochloride to 2-mercapto-5-methoxybenzimidazole and potassium hydroxide is 1:1.2:0.1;

[0037] 2) Mix 630 g of omeprazole sulfide obtained in step 1) with the compound represented by formula A and the inorganic metal salt in 5 L of acetone. The m...

Embodiment 3

[0041] A preparation method of esomeprazole magnesium trihydrate, comprising the following steps:

[0042] 1) In the presence of sodium carbonate, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-mercapto-5-methoxybenzimidazole 540g in 4LTHF Carry out reflux reaction for 4 hours to obtain omeprazole sulfide, and then refine it. The refining process is as follows: first dissolve omeprazole sulfide in 1.5L acetonitrile at 65°C, then drop 3.7L petroleum ether into the solution at 0.15°C Cool down to 12°C at a speed of 1 / s, let it stand for 1 hour, centrifuge and filter to obtain 790g of refined omeprazole sulfide, the yield is 83.5%, and the purity is 99.58%. 2-Chloromethyl-3,5-di The molar ratio of methyl-4-methoxypyridine hydrochloride to 2-mercapto-5-methoxybenzimidazole and sodium carbonate is 1:1:0.15;

[0043] 2) Mix 630 g of omeprazole sulfide obtained in step 1) with the compound represented by formula A and the inorganic metal salt in 5 L of aceton...

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Abstract

The invention discloses a preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases. The preparation method comprises the following steps: (1) in the presence of an alkaline compound, carrying out a reflowing reaction on 2-chloromethyl-3,5-dimethyl-4-methoxylpyridine hydrochloride and 2-sulfydryl-5-methoxylbenzimidazole in THF (Tetrahydrofuran) to obtain omeprazole thioether; (2) mixing the omeprazole thioether with a compound represented by formula A and an inorganic metal salt in acetone to obtain a mixture B; (3) adding an oxidant into the mixture B to carry out an oxidization reaction at a temperature of 10 to 50 DEG C; after the reaction is finished, adding a potassium hydroxide methanol solution to obtain esomeprazole potassium; (4) mixing the esomeprazole potassium and anhydrous magnesium chloride in methanol, and stirring and reacting; then centrifuging and separating to obtain the esomeprazole magnesium trihydrate, wherein the inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal salt. The preparation method has high yield, good selectivity and high reaction efficiency and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of esomeprazole magnesium trihydrate. Background technique [0002] Esomeprazole magnesium (esomeprazolemagnesium), is the S-isomer magnesium salt preparation of omeprazole listed by AstraZeneca, Sweden in 1988, S-(-)-5-methoxy-2-[(4- Methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ylmagnesium, present in the formulation as esomeprazole magnesium trihydrate. As a new type of proton pump inhibitor, esomeprazole magnesium can inhibit the activity of H / K-ATPase, and is used to treat digestive system diseases such as gastric ulcer, duodenal ulcer and reflux esophagitis caused by excessive gastric acid secretion . [0003] At present, esomeprazole salt is mainly obtained by esomeprazole salification, therefore, the preparation method of esomeprazole not only affects the yield and the purity of esomeprazole, but also affects the yield and purity of es...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 陈令浩
Owner QINGDAO CENT HOSPITAL
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