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Preparation process of (S)-pantoprazole sodium

A technology for preparing levopantoprazole sodium and its preparation process, which is applied in the field of drug synthesis, can solve the problems of complex post-processing, expensive titanium reagents, and low yield, and achieve the goal of avoiding post-processing purification steps, facilitating industrial production, and easy operation Effect

Inactive Publication Date: 2017-05-10
QINGDAO YUNTIAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Although selective chemical synthesis has shown advantages over chiral resolution, the above-mentioned synthesis method has problems such as low enantioselectivity, low yield, expensive titanium reagent, and complicated post-treatment; in addition, the above-mentioned method also has There is a situation where pantothioether is over-oxidized to produce a by-product sulfone, and purification is extremely difficult

Method used

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  • Preparation process of (S)-pantoprazole sodium

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Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of L-pantoprazole

[0032] 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzimidazole 36.7g (100mmol) and quinine benzyl bromide Add 14.8g (30mmol) of quaternary ammonium salt into the reactor in 150ml1,4-dioxane, replace with nitrogen three times, stir and mix for 30min, then add 14.8g (200mmol) of dimethyldioxirane, and cool down Stir and contact reaction at 10°C for 3 hours, filter the reaction solution after cooling, concentrate the filtrate, wash with water, then recrystallize from petroleum ether, and dry to obtain 37.4 g of L-pantoprazole with a yield of 97.5% and an ee value of 98.96%.

Embodiment 2

[0034] Preparation of L-pantoprazole

[0035] 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzimidazole 36.7g (100mmol) and quinine benzyl bromide Add 24.7g (50mmol) of quaternary ammonium salt into 150ml 1,4-dioxane, replace with nitrogen three times, stir and mix for 30min, then add 14.8g (200mmol) of dimethyldioxirane, cool to 5°C and stir After 2 hours of contact reaction, the reaction liquid was cooled and filtered, the filtrate was concentrated, washed with water, then recrystallized from petroleum ether, and dried to obtain 37.6 g of (S)-pantoprazole with a yield of 98.1% and an ee value of 99.12%.

Embodiment 3

[0037] Preparation of L-pantoprazole

[0038] 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzimidazole 36.7g (100mmol) and quinine benzyl bromide Add 29.7g (60mmol) of quaternary ammonium salt into 140ml 1,4-dioxane, replace with nitrogen three times, stir and mix for 30min, then add 22.2g (300mmol) of dimethyldioxirane, and cool down to 20°C Stirring and contact reaction for 4 hours, the reaction solution was cooled and filtered, the filtrate was concentrated, washed with water, then recrystallized from petroleum ether, and dried to obtain 37.3 g of L-pantoprazole with a yield of 97.4% and an ee value of 98.82%.

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Abstract

The invention discloses a preparation process of (S)-pantoprazole sodium. The preparation process comprises steps as follows: 1), 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl] sulfur]-1H-benzimidazole and chiral quaternary ammonium salt are added to an organic solvent and are stirred and mixed for 30 min under the protection of nitrogen, an ether solution of dimethyldioxirane is dropwise added, the mixture reacts continuously, and (S)-pantoprazole is obtained; 2), (S)-pantoprazole and sodium alcoholate react, and (S)-pantoprazole sodium is obtained. According to the preparation method of (S)-pantoprazole sodium, the yield of (S)-pantoprazole sodium is quite high, stereoselectivity is high, excessively oxidized sulfone products cannot be produced, complicated aftertreatment and purification steps are omitted, conditions are mild, and the process is simple and convenient to operate and is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation process of L-pantoprazole sodium. Background technique [0002] Pantoprazole sodium is based on the principle of Me too drug design on the basis of omeprazole, and the drug with better efficacy is found after the parent structure is modified. Pantoprazole sodium is developed by the German Byk Gulden company and has Listed in more than 20 countries and regions such as the United States, the United Kingdom, and Germany, it is the third proton pump inhibitor in the world after omeprazole and lansoprazole. to severe reflux esophagitis. Compared with other proton pump inhibitors, it is stable under weak acid conditions, and it is quickly activated under strong acid conditions and has little interaction with other drugs. Compared with omeprazole, it is 7 times higher, and its safety and effectiveness are higher than that of omeprazole and lansoprazole when it i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/07
Inventor 许士娜
Owner QINGDAO YUNTIAN BIOTECH