Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof

A technology of benzimidazole and compound, which is applied in the field of preparation of benzimidazole-type proton pump inhibitors and their precursors, can solve problems such as unstable yield and product purity, cumbersome post-treatment, difficult crystallization, etc., and achieve reaction efficiency and Good selectivity, simple and easy post-processing, and solve the cumbersome effect of post-processing

Active Publication Date: 2008-06-11
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method overcomes the disadvantages of poor reproducibility, unstable yield and product purity of the previous method, and solves the problems of cumbersome post-processing and difficult crystallization.

Method used

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  • Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof
  • Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof
  • Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Add 3.62g (0.02 moles) of 5-methoxy-2-mercapto-1H-benzimidazole, 6 mL of water, 1.63 g (0.04 moles) of sodium hydroxide, and 30 mL of ethanol into the reaction flask. After stirring and dissolving, add 3% Molar equivalent of SDS, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride, heat and stir to reflux for 2 hours. After the reaction is complete, filter, add water to the filtrate, adjust the pH to 7 with 36% acetic acid, extract with dichloromethane, wash the organic layer with water, evaporate the organic layer to dryness, add acetone, add petroleum ether, stir well, freeze, filter, and dry , to obtain 4.47 g of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methylthio]-1H-benzimidazole, yield 69.7%, The content is 95.6%.

Embodiment 2

[0054] Add 3.62g (0.02 moles) of 5-methoxy-2-mercapto-1H-benzimidazole, 6 mL of water, 1.63 g (0.04 moles) of sodium hydroxide, 30 mL of ethanol into the reaction flask, stir to dissolve, then add 5% To the molar equivalent of CTAB, add 4.44g (0.02 moles) of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride, and heat, stir and reflux for 2 hours. After the reaction is complete, filter, add water to the filtrate, adjust the pH to 7 with 36% acetic acid, extract with dichloromethane, wash the organic layer with water, evaporate the organic layer to dryness, add acetone, add petroleum ether, stir well, freeze, filter, and dry , to obtain 4.29 g of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methylthio]-1H-benzimidazole, yield 66.9%, Content 94.5%.

Embodiment 3

[0056] Add 3.62g (0.02 moles) of 5-methoxy-2-mercapto-1H-benzimidazole, 6 mL of water, 1.63 g (0.04 moles) of sodium hydroxide, and 30 mL of ethanol into the reaction flask. After stirring and dissolving, add 3% Add 4.44 g (0.02 moles) of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride to the molar equivalent neutral surfactant TritonX-100, and heat, stir and reflux for 2 hours. After the reaction is complete, filter, add water to the filtrate, adjust the pH to 7 with 36% acetic acid, extract with dichloromethane, wash the organic layer with water, evaporate the organic layer to dryness, add acetone, add petroleum ether, stir well, freeze, filter, and dry 5.65 g of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methylthio]-1H-benzimidazole was obtained with a yield of 86.7%, Content 98.9%

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Abstract

The provided preparation, separation and purification method for benzimidazole-type proton pump inhibitor and its precursor, such as omeprazole, rabeprazole, lansoprazole, and ilaprazole comprises: for the first time, adding surfactant or phase-transfer catalyst in the synthesis process to speed up and promote the reaction more complete. This invention has well reaction efficiency and selectivity to overcome the defects in prior art and benefit to post-treatment and crystallization.

Description

technical field [0001] The invention provides a kind of preparation benzimidazole type proton pump inhibitor and precursor thereof, such as the improved preparation and preparation of omeprazole, rabeprazole, lansoprazole, ilaprazole, pantoprazole etc. Separation and purification methods. Background technique [0002] Compounds with a benzimidazole structure headed by omeprazole can inhibit acid secretion of gastric parietal cells caused by any stimulation, and are a good class of anti-ulcer drugs. [0003] In 1981, US 4255431 disclosed the preparation method of benzimidazole compounds such as omeprazole, and reported 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridine Base)-methylthio]-1H-benzimidazole reacts with m-chloroperoxybenzoic acid in dichloromethane solution to generate omeprazole and m-chlorobenzoic acid. Subsequently, several patents improved the preparation and separation and purification methods of benzimidazole compounds. CN 91103923.6 (WO 91 / 18895) changed th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
Inventor 邓金根朱槿吴君王启卫黄秋亚朱剑平
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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