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Preparation method of esomeprazole magnesium trihydrate

A technology of esomeprazole magnesium trihydrate and meprazole magnesium trihydrate, which is applied in the field of drug synthesis, can solve the problems that the final product is difficult to meet the quality standard and the crystal water is easy to detach, and achieves high stereoselectivity and Specificity, ease of operation, and productivity-enhancing effects

Active Publication Date: 2015-11-25
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because esomeprazole magnesium trihydrate contains three waters of crystallization, if the final product is refined and purified with a solvent, the water of crystallization will be easily separated. azole or esomezole potassium for purification, otherwise the final product is difficult to meet the quality standard

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of esomeprazole

[0031] Add 21.4g (100mmol) of (R,R)-1,2-diphenyl-1,2-ethanediol into 1000ml of dichloromethane, and add 14.2g (50mmol) of tetraisopropoxytitanium dropwise under stirring , 12g isopropanol (200mmol), add 329.42g omeprazole sulfide (1mol) after dissolving clear, after stirring and dissolving at room temperature, cool to 5-10 ℃, dropwise add 70% tert-butyl hydroperoxide aqueous solution ( 2.1mol), the mixture was stirred at 5-10°C for 2.0-2.5 hours, 100ml of ammonia (10%) solution was added to terminate the reaction, and 10% acetic acid aqueous solution was added to adjust the pH=8-9, the layers were separated, and the water phase was dichloromethane Extracted 3 times, combined organic phase, Na 2 SO 4After drying, filtering and concentrating, 304.8 g of white solid was obtained, and the yield was 88.2%. Melting point: 168.5~170.3 ℃; Purity 98.43%, impurity sulfone 0.78%, [HPLC method: chromatographic column ZorbaxSB-C column (4.6minx150mm,...

Embodiment 2

[0037] Preparation of esomeprazole

[0038] Add 2.14g (10mmol) of (R,R)-1,2-diphenyl-1,2-ethanediol into 100ml of dichloromethane, and add 1.42g (5mmol) of titanium tetraisopropoxide dropwise under stirring , 1.2g isopropanol (20mmol), add 33.0g omeprazole sulfide (0.1mol) after dissolving, stir and dissolve at room temperature, cool to 5-10°C, add dropwise 70% tert-butyl hydroperoxide Aqueous solution (0.2mol), the mixture was stirred at 5-10°C for 2.0-2.5 hours, 10ml of ammonia (10%) solution was added to terminate the reaction, and 10% acetic acid aqueous solution was added to adjust the pH=8-9, the layers were separated, and the aqueous phase was mixed with two Chloromethane extraction 3 times, combined organic phase, Na 2 SO 4 Dry, filter, and concentrate to obtain 31.6 g of white solid, with a yield of 91.5%. The purity is 98.55%, and the impurity sulfone is 0.56%. ee value 99.65%

Embodiment 3

[0040] Preparation of esomeprazole

[0041] Add 3.21g (15mmol) of (R,R)-1,2-diphenyl-1,2-ethanediol into 100ml of dichloromethane, and add 2.13g (7.5mmol) of tetraisopropoxytitanium dropwise under stirring. ), 1.8g isopropanol (30mmol), after dissolving, add 33.0g omeprazole sulfide (0.1mol), stir and dissolve at room temperature, cool to 5-10°C, add dropwise 70% tert-butyl peroxide Aqueous hydrogen solution (0.21mol), stir the mixture at 5-10°C for 2.0-2.5 hours, add 12ml ammonia water (10%) solution to terminate the reaction, add 10% acetic acid aqueous solution to adjust pH=8-9, separate layers, use for water phase Dichloromethane extracted 3 times, combined organic phase, Na 2 SO 4 After drying, filtering and concentrating, 32.2 g of white solid was obtained, yield 93.22%; purity 98.08%, impurity sulfone 0.63%; ee value 99.43%.

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Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an esomeprazole magnesium trihydrate. The preparation method comprises steps as follows: 1) 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio-1H-benzimidazole (ufiprazole) is oxidized into esomeprazole with an oxidizing agent in an organic solvent in the presence of (R,R)-1,2-diphenyl-1,2-glycol, titanium alkoxide and isopropyl alcohol; 2) esomeprazole sodium is prepared through the reaction of the esomeprazole with sodium methoxide; 3) the esomeprazole sodium and magnesium chloride have salt exchange in methanol to produce the esomeprazole magnesium trihydrate. The method has the characteristics of high stereoselectivity and specificity and the like, can increase the yield of the target product, and is easy to operate and suitable for industrial 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), the chemical name is 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzo Imidazol-1-yl magnesium is a magnesium salt preparation of (S)-(-)-type single enantiomer of omeprazole developed by AstraZeneca in Sweden, and exists in the form of esomeprazole magnesium trihydrate middle. This product is a new type of proton pump inhibitor, which can inhibit the activity of H / K-ATPase. It is mainly used in the treatment of digestive system diseases such as gastric ulcer, duodenal ulcer and reflux esophagitis caused by excessive gastric acid secretion. . [0003] The preparation methods of esomeprazole include: racemic body omeprazole resolution method, omeprazole sulfide asymmetric catalytic oxidation method and biochemical oxidation me...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 杨静侯孝龙朱丽萍
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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