Preparation method for esomeprazole

A technology of esomeprazole and methoxybenzimidazole, which is applied in the field of high-efficiency enzyme catalyst preparation of esomeprazole, can solve the problems of low selectivity, difficulty in realizing industrial production, complicated operation, etc., and achieve the reduction of impurity nitrogen Oxides, improved yield and purity, and ease of industrial production

Inactive Publication Date: 2018-04-10
JIANGSU ZHONGBANG PHARMA
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Problems solved by technology

[0004] At present, esomeprazole salt is mainly obtained by esomeprazole salification, therefore, the preparation method of esomeprazole not only affects the purity of esomeprazole, but also affects the purity of esomeprazole salt
The preparation methods of esomeprazole include: racemic body omeprazole resolution method, omeprazole sulfide asymmetric catalytic oxidation method and biochemical oxidation method, but because racemic body omeprazole The resolution method will waste half of the omeprazole, causing environmental pollution and economic loss, and the price of the optically active resolution agent is also relatively expensive, so the large-scale use of this resolution method in industry is limited; biochemical Due to the complicated operation and low selectivity of the oxidation method, its application is also limited; the common method for preparing esomeprazole is the asymmetric catalytic oxidation method of omeprazole sulfide, for example: International Patent Application WO96 / 02535 Disclosed is a method for obtaining S-omeprazole by oxidizing omeprazole sulfide with hydrogen peroxide derivatives in the presence of chiral bidentate ligand diethyl tartrate, titanium metal complex and alkali; Patent application WO03 / 089408 describes the oxidation of omeprazole sulfide under the catalysis of chiral monodentate (S)-(+)-mandelate and titanium or vanadium complexes in the presence of a base to obtain L-oxime The method of meprazole
However, a large amount of impurity nitrogen oxides and sulfones are easily produced in the above-mentioned preparation process, and the pollution problem of heavy metals is also a problem that cannot be ignored, which greatly affects the chemical purity and optical purity of esomeprazole, making it difficult to realize industrial production

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  • Preparation method for esomeprazole
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  • Preparation method for esomeprazole

Examples

Experimental program
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Effect test

Embodiment 1

[0052] (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (Exome Prazole) preparation

[0053] Get 100 grams of methanol and pour it into a 500 milliliter three-necked flask, add 8.8 grams (220 mmol) of sodium hydroxide, then put 23.0 grams (130 mmol) of 2-mercapto-5-methoxybenzimidazole into the above-mentioned sodium hydroxide Stir in the methanol solution to make it dissolve, then add 24.0 g (110 mmol) 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride into the reaction solution, after the addition, heat up Stir the reaction at 50°C for 4 hours, and determine the end point of the reaction by TLC (the developer is V dichloromethane: V methanol = 30:1). After the reaction is completed, add 200 grams of drinking water dropwise to crystallize overnight, then filter, wash and dry to obtain 34.1 g of the compound having the structure of formula (I).

[0054] The purity of the compound with the structure of formula (I) measured by HPLC is 99.8%...

Embodiment 2

[0061] (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole potassium (Esso Meprazole potassium) preparation

[0062] Get 100 grams of ethanol and pour it into a 500 milliliter three-necked bottle, add 12.32 grams (220 mmol) of potassium hydroxide, then put 23.0 grams (130 mmol) of 2-mercapto-5-methoxybenzimidazole into the above potassium hydroxide Stir in the ethanol solution to dissolve it, then add 24.0 g (110 mmol) 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride into the reaction solution, after the addition, continue React at 40°C for 3 hours, TLC determines the reaction end point (developing agent is V dichloromethane: V methanol = 30: 1), after the reaction is completed, add 200 grams of drinking water dropwise to crystallize overnight, then filter, wash and dry to obtain the product with 33.7 grams of the compound of formula (I).

[0063] The purity of the compound with the structure of formula (I) measured by HPLC is 99.8%

[00...

Embodiment 3

[0070] (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole potassium (Esso Meprazole potassium) preparation

[0071] Get 300 grams of acetone and pour it into a 1000 milliliter three-necked bottle, add 69.96 grams (660 mmol) of sodium carbonate, then drop 69.0 grams (390 mmol) of 2-mercapto-5-methoxybenzimidazole into the above-mentioned sodium carbonate acetone solution Stir in medium to dissolve it, then add 72.0 grams (330 mmol) of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride into the reaction solution, after the addition, continue at 55 ℃ for 5 hours, TLC to determine the reaction end point (developing agent is V dichloromethane: V methanol = 30: 1), after the completion of the reaction, add 600 grams of drinking water dropwise to crystallize overnight, then filter, wash and dry to obtain formula ( 100.2 grams of the compound of structure I).

[0072] The purity of the compound with the structure of formula (I) measured by HPLC is ...

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Abstract

The invention discloses a method for preparing esomeprazole, belonging to the technical field of medicine. According to the invention, 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride and 2-mercapto-5-methoxybenzimidazole are used as starting materials and are subjected to condensation and oxidation so as to prepare an esomeprazole salt. The method has good reproducibility, and is simple to operate, easy for realizing industrial production and mild in preparation conditions; and the production of impurity nitrogen oxide and sulfone (peroxide) during the preparation is reduced, and the yield and purity of the esomeprazole salt are improved.

Description

Technical field: [0001] The invention relates to the technical field of medicine, in particular to a method for preparing esomeprazole with an efficient enzyme catalyst. Background technique: [0002] Esomeprazole is the S-isomer of omeprazole, and its chemical name is: (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl- 2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, the molecular formula is: C17H19N3O3S. Esomeprazole belongs to isomeric proton pump inhibitors, and proton pump inhibitors (PPIs) are the drugs of choice for the treatment of acid-related diseases such as peptic ulcer and gastroesophageal reflux disease. [0003] Esomeprazole salt is obtained by forming esomeprazole into a salt. Esomeprazole salt can reduce the irritation to the body, and has good solubility in the body, improving bioavailability, so that it can produce More ideal pharmacological effects, common esomeprazole salts mainly include esomeprazole sodium, esomeprazole potassium, and esomeprazole magnesium. [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07B2200/07C07D401/12
Inventor 吴四清蒋海松王红喜史凌云黄双徐强
Owner JIANGSU ZHONGBANG PHARMA
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