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Preparation method of benzimidazole proton pump inhibitor intermediate

A proton pump inhibitor, benzimidazole type technology is applied in the field of preparation of benzimidazole type proton pump inhibitor intermediates, can solve the problems of cumbersome operation, low total yield and high cost, and achieves high product purity and high reaction efficiency. The effect of good yield and low equipment requirements

Inactive Publication Date: 2014-03-26
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthesis method is loaded down with trivial details operation, and overall yield is low, and cost is high

Method used

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  • Preparation method of benzimidazole proton pump inhibitor intermediate
  • Preparation method of benzimidazole proton pump inhibitor intermediate
  • Preparation method of benzimidazole proton pump inhibitor intermediate

Examples

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Effect test

Embodiment 1

[0025] Synthesis of rabeprazole intermediate 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole

[0026] In a 250ml three-necked flask, dissolve 5.51g (0.026mol) of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide in 25ml of benzene, and stir at a constant temperature of 80°C. Take 6.61g (0.043mol) of phosphorus oxychloride as a chlorination agent and 4.20g (0.041mol) of triethylamine as an acid-binding agent, and dilute to 20ml with dichloromethane respectively. After the dichloromethane solution of phosphorus oxychloride 2ml was added dropwise, the dichloromethane solution of triethylamine was added dropwise at the same rate. After 30 minutes, the dropwise addition was completed, and the reaction was stirred at a constant temperature for 2.5 hours. TLC detected that the reaction was complete, and the reaction was stopped. The pH was adjusted to 7 with saturated sodium carbonate solution, filtered, extracted with chloroform, dried, and the organic la...

Embodiment 2

[0029] Synthesis of omeprazole intermediate 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole

[0030] In a 250ml three-neck flask, dissolve 4.70g (0.028mol) of 4-methoxy-2,3,5-trimethyl-N-pyridine oxide in 25ml of benzene, and stir at a constant temperature of 75°C. Take 6.81g (0.044mol) of phosphorus oxychloride as a chlorination agent and 3.95g (0.039mol) of triethylamine as an acid-binding agent, and dilute to 25ml with dichloromethane respectively. After the dichloromethane solution of phosphorus oxychloride 3ml was added dropwise, the dichloromethane solution of triethylamine was added dropwise at the same rate. The dropwise addition was completed in about 30 minutes, and the reaction was performed at a constant temperature for 2 hours. TLC detected that the reaction was complete, and the reaction was stopped. The pH was adjusted to 7 with saturated sodium carbonate solution, filtered, extracted with chloroform, dried, and the organic layer wa...

Embodiment 3

[0033]Synthesis of lansoprazole intermediate 2-{[4-(2,2,2-trifluoromethoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole

[0034] Take 6.64g (0.03mol) of 4-(2,2,2-trifluoroethoxy)-2,3-dimethyl-N-pyridine oxide in a 250ml three-necked flask, add 25ml of benzene, and stir at a constant temperature of 90°C . Take 7.34g (0.048mol) of phosphorus oxychloride as a chlorination agent and 4.24g (0.042mol) of triethylamine as an acid-binding agent, and dilute to 25ml with dichloromethane respectively. After the dichloromethane solution of phosphorus oxychloride 3ml was added dropwise, the dichloromethane solution of triethylamine was added dropwise at the same rate. After about 40 minutes of dropwise addition, continue to stir and react for 3 hours, TLC detects that the reaction is complete, stop the reaction, adjust the pH to 7 with saturated sodium carbonate solution, filter, extract with chloroform, dry, and evaporate the organic layer to obtain 2-chloromethyl- 4-(2,2,2-Triflu...

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Abstract

The invention provides a preparation method of a benzimidazole proton pump inhibitor intermediate. The method comprises the following steps: (1)dissolving 2-picoline oxynitride derivative into an organic solvent, stirring, using dichloromethane to perform metered volume on a chlorinated agent and an acid-binding agent, dropwise adding the chlorinated agent solution firstly, then simultaneously dropwise adding the acid-binding agent solution, reacting, adjusting pH, filtering, extracting, drying and distilling to obtain 2-chlorine picoline derivative; (2)dissolving 2-sulfydryl-1-H-benzimidazole derivative into a sodium hydroxide ethanol solution, adding 2-chlorine picoline derivative, stirring for reaction, filtering, extracting by using dichloromethane, drying, distilling the organic layer, adding ethyl acetate, then adding petroleum ether, stirring, freezing crystallization, filtering, washing and drying to obtain the benzimidazole proton pump inhibitor intermediate. The invention has the following advantages: (1) the chlorinated performance of phosphorus oxychloride is excellent, other byproducts are not generated; (2) the reaction conversion rate is improved; (3) the reaction steps are simplified, and the product loss is reduced.

Description

technical field [0001] The invention provides a preparation method of a benzimidazole type proton pump inhibitor intermediate. Background technique [0002] Studies have shown that excessive gastric acid secretion is the most important cause of digestive system diseases. The final step in gastric acid secretion is the intraparietal proton pump (H + , K + -ATPase) drives the exchange of intracellular hydrogen ions with potassium ions in the tubules to secrete acid. Proton pump inhibitors can effectively block the proton pump. Compounds with a benzimidazole structure headed by omeprazole can effectively inhibit the secretion of gastric acid. It is different and has more advantages, such as good acid suppression effect at night, fast onset, strong acid suppression effect and long time, convenient to take, and can effectively inhibit the secretion of basic gastric acid and histamine, acetylcholine, gastrin and food Acid secretion caused by stimulation. [0003] In 1981, aft...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 肖艳华冯睿杰任浩
Owner WUHAN INSTITUTE OF TECHNOLOGY
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