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Method for synthesis and refining of esomeprazole sodium

A technology of esomeprazole sodium and benzimidazole is applied in the field of synthesis and purification of esomeprazole sodium, can solve the problems of difficult industrial scale-up production, high raw material cost, low product yield and the like, and achieves a reduction in production Cost, high product yield, and the effect of shortening the reaction time

Inactive Publication Date: 2016-11-23
TIANJIN HANRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to solve the raw material cost that exists in the synthesis of esomeprazole sodium in the above prior art, the product yield is low, the optical purity is low, the problem that is difficult for industrial scale-up production, the invention provides a kind of simple operation, stable and reliable process, Asymmetric oxidation has high selectivity, high product yield and high optical purity (ee% value), which is very suitable for the production method of esomeprazole sodium in large-scale industrialization

Method used

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  • Method for synthesis and refining of esomeprazole sodium
  • Method for synthesis and refining of esomeprazole sodium
  • Method for synthesis and refining of esomeprazole sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0075] Preparation of intermediates:

[0076] Add 5.67g of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole to a 100mL three-necked flask, add toluene 25mL, stirred, heated to 60°C, then sequentially added 90uL of purified water, 2.3g of D-diethyl tartrate and 28g of tetraisopropyl titanate, stirred for 1h, and cooled down. At T=27°C, 1.89 g of N,N-diisopropylethylamine was added, and after 15 minutes, 2.8 mL of cumene hydroperoxide was slowly added dropwise within 30 minutes. After the reaction, TLC detection showed that a small amount of raw materials remained. Extract 3 times with 12% ammonia water, combine the water phases, add dichloromethane, then adjust the pH to about 8 with acetic acid, separate the liquids, wash the organic phase with 20 mL each of purified water and saturated saline, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain 5.56 g of brown oil.

[0077] Preparation of esomeprazole sodium crude product:

[0...

Embodiment 2

[0082] Preparation of intermediates:

[0083] Add 5.67g of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole to a 100mL three-necked flask, add toluene 25mL, stirred, heated to 65°C, then sequentially added 90uL of purified water, 2.3g of diethyl D-tartrate and 28g of tetraisopropyl titanate, stirred for 1h, and cooled down. When T=33°C, 1.4 g of N,N-diisopropylethylamine was added, and after 15 minutes, 1.89 mL of cumene hydroperoxide was slowly added dropwise within 30 minutes. After the reaction, TLC detection showed that a small amount of raw materials remained. Extract 3 times with 12% ammonia water, combine the water phases, add dichloromethane, then adjust the pH to about 8 with acetic acid, separate the liquids, wash the organic phase with 20 mL each of purified water and saturated saline, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain 5.55 g of brown oil.

[0084] Preparation of esomeprazole sodium crude product:

...

Embodiment 3

[0089] Preparation of intermediates:

[0090] Add 5.67g of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole to a 100mL three-necked flask, add toluene 25mL, stirred, heated to 65°C, then sequentially added 90uL of purified water, 2.3g of diethyl D-tartrate and 28g of tetraisopropyl titanate, stirred for 1h, and cooled down. At T=30°C, 1.6 g of N,N-diisopropylethylamine was added, and after 15 minutes, 2.5 mL of cumene hydroperoxide was slowly added dropwise within 30 minutes. After the reaction, TLC detection showed that a small amount of raw materials remained. Extract 3 times with 12% ammonia water, combine the water phases, add dichloromethane, then adjust the pH to about 8 with acetic acid, separate the liquids, wash the organic phase with 20 mL each of purified water and saturated saline, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain 5.6 g of brown oil.

[0091] Preparation of esomeprazole sodium crude product:

[009...

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PUM

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Abstract

The invention relates to the field of chemical synthesis, and particularly relates to a new method for synthesis and refining of esomeprazole sodium; with omeprazole sulfide as a raw material, and through selection of the specific solvent type and proportion in the preparation process, the method has the advantages of simple operation, stable and reliable technology, high asymmetric oxidation selectivity and high yield of the obtained product, and high optical purity (ee% value), and is the production method quite suitable for large-scale industrialization of esomeprazole sodium.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a new method for the synthesis and purification of esomeprazole sodium. Background technique [0002] Esomeprazole sodium, full name: (S)-5-methoxy-2{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl} -1H-benzimidazole sodium, English name: Esomeprazole sodium, Esomeprazole sodium for injection was approved by the FDA on April 3, 2007 for listing on AstraZeneca AB. Esomeprazole sodium is the S isomer of omeprazole, the first proton pump inhibitor developed as an isomer for the treatment of short-term gastroesophageal reflux. Its structure is as follows: [0003] [0004] So far, the synthetic patent literature of esomeprazole has been very rich. Through our investigation and analysis, we found that there are three main synthetic routes: [0005] 1. Resolution of racemate omeprazole by means of chiral resolution reagents (such as WO 9427988, WO 04 / 002982, etc.) [0006] 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 严洁
Owner TIANJIN HANRUI PHARMA
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