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Preparation method of esomeprazole sodium thioether intermediate

An intermediate, the technology of azole thioether, applied in the field of pharmaceutical preparation, can solve the problems of inability to remove water, affect the high selectivity of selective oxidation reaction, etc., and achieve the effect of high stability, high selectivity and low water content

Active Publication Date: 2019-07-23
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that the compound of formula I is easy to form hydrate with water, and the water cannot be removed by drying. The water in the hydrate is far more than the water required for the selective oxidation reaction, which affects the high selectivity of the selective oxidation reaction.

Method used

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  • Preparation method of esomeprazole sodium thioether intermediate
  • Preparation method of esomeprazole sodium thioether intermediate
  • Preparation method of esomeprazole sodium thioether intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Mix methanol (48mL), 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (10.0g), 2-mercapto-5-methoxybenzimidazole (8.2g) , Sodium hydroxide (4.8g) was dissolved in purified water (10mL) and added to the reaction flask, heated to 60°C for 1 hour. The temperature was lowered to 25°C, and purified water (40 ml) was added to the reaction solution. Adjust the pH to 9-10 with hydrochloric acid. The reaction solution was extracted with chloroform (50ml×2) and separated. The organic layer was dried with anhydrous sodium sulfate and filtered. Cumene (30ml) was added to the filtrate and concentrated under reduced pressure to a remaining volume of 20mL. Cumene (30 ml) and diethyl ether (100 ml) were added to the residue, and the mixture was stirred and crystallized at 10°C for 8 hours. After filtration, the filter cake was vacuum dried to obtain the omeprazole intermediate (14.2 g). The yield is 96%, and the moisture content is 0.03%.

Embodiment 2

[0038] Add dimethylformamide (48mL), 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (10.0g), 2-mercapto-5-methoxybenzimidazole (8.2g), sodium hydroxide (4.8g) was dissolved in purified water (10mL) and added to the reaction flask, heated to 70°C for 1 hour. The temperature was lowered to 25°C, and purified water (40 ml) was added to the reaction solution. Adjust the pH to 10-11 with hydrochloric acid. The reaction solution was extracted with chloroform (50ml×2) and separated. The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. During the process, xylene (30ml) was added, and the concentration was continued to the remaining volume of 20mL. Xylene (30 ml) and isopropyl ether (100 ml) were added to the residue, and the mixture was stirred and crystallized at 10°C for 8 hours. After filtration, the filter cake was dried under vacuum to obtain the omeprazole intermediate (14.1 g). The yield is ...

Embodiment 3

[0040] Combine 1,4 dioxane (50 mL), 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (10.0g), 2-mercapto-5-methoxybenzene The bisimidazole (8.2g) and sodium hydroxide (4.8g) were dissolved in purified water (15mL) and added to the reaction flask, and the temperature was raised to 80°C for 1 hour. The temperature was lowered to 25°C, and purified water (35 ml) was added to the reaction solution. Adjust the pH value to 8-9 with hydrochloric acid. The reaction solution was extracted with dichloromethane (50ml×2) and separated. The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After completion, toluene (30ml) was added and the concentration was continued to the remaining volume of 20mL. Toluene (30 ml) and n-heptane (100 ml) were added to the residue, and the mixture was stirred and crystallized at 10°C for 8 hours. After filtration, the filter cake was dried under vacuum to obtain the omeprazo...

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Abstract

The invention relates to a preparation method of an esomeprazole sodium thioether intermediate. Through the adjustment of a process method, the water content of the esomeprazole sodium thioether intermediate 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfanyl]-1H-benzimidazole is controlled below 0.03%, which facilitates more effective control of the water content in a subsequent oxidation reaction system and ensures the high selectivity, high stability, strong controllability and reproducibility of a selective oxidation reaction. The preparation method of the invention has good reproducibility and is more beneficial to large-scale production.

Description

Technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl) intermediate of esomeprazole sulfide Methyl]sulfanyl]-1H-benzimidazole preparation method. Background technique [0002] Esomeprazole Sodium, developed by AstraZeneca, has been marketed in the United States, the European Union, Japan, and China and other countries. It is a proton pump inhibitor for the treatment of gastric ulcer and other diseases. [0003] The compound 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfanyl]-1H-benzimidazole (formula I) is a synthetic AI An important intermediate of Someprazole Sodium and Esomeprazole Magnesium. [0004] [0005] The thioether of this compound is selectively oxidized to sulfoxide of S configuration. The current common oxidation reaction conditions are: cumene hydrogen peroxide / D-(-)-diethyl tartrate / tetraisopropyl titanium oxide / The classic combination of water, "Rece...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 王俊亮余雷郭彦亮王永恒尹坤洲
Owner JIANGSU HANSOH PHARMA CO LTD
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