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Method for preparing esomeprazole impurity

A technology for esomeprazole and impurities, which is applied in the field of organic chemical synthesis, can solve the problems of few synthesis routes of benzimidazole, low ee value of the product, cumbersome operation, etc., and achieves simple operation, wide range of sources, and comprehensive synthesis routes short effect

Active Publication Date: 2018-09-04
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 5-methoxy-2-[( S )-[(4-Chloro-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1 H - There are not many alternative synthetic routes for benzimidazole, and the entire synthetic route has not been reported in the literature
[0013] Patent EP1718636B1 reported that the compound of formula III was asymmetrically oxidized to obtain the compound of formula II. The ee value of the reaction solution was 75%. The crude product was purified by column chromatography and then purified by acetonitrile to obtain the product with an ee value of 51%. The ee value of the product obtained by acetonitrile recrystallization is 92.5%, which shows that the product ee value is low and the operation is cumbersome, and the yield is low

Method used

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  • Method for preparing esomeprazole impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0056] 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylmercapto]-1 H -The preparation of benzimidazole (III)

[0057] Add 10g of the compound represented by formula VII and 50g of toluene to the three-necked flask, maintain 110~115°C for 12hrs, and detect the reaction solution by TLC until the reaction is complete to obtain 2-chloromethyl-4-hydroxy-3,5-dimethyl base pyridine (VI) reaction solution. Cool down to room temperature, add 13.8g of phosphorus oxychloride, maintain 100~110°C for 3 hours, detect the reaction solution with thin layer until the reaction is complete, lower the temperature, control the temperature to ≤20°C, slowly add 55g of water, add 100g of methanol, slowly add 20 %NaOH aqueous solution 70g (NaOH is 14g), after adding, slowly add 2-mercapto-5-methoxybenzimidazole (IV) 8.5g, raise the temperature to 45°C and react for 3hr, TLC detection of the reaction solution until the reaction is complete, add The reaction solution was washed with water, separat...

Embodiment 2

[0059] 5-methoxy-2-[( S )-[(4-Chloro-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1 H - preparation of benzimidazole (II)

[0060] Get the 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl) methylmercapto]-1 prepared in Example 1 H - Benzimidazole (III) 10g, add 45g toluene, 2.4g tetraisopropyl titanate, 2.8g L-diethyl tartrate, 2.5g N,N-diisopropylethylamine, heat up to 60°C and stir to dissolve, keep warm React for 30 minutes, lower the temperature, maintain the temperature at 10~15°C, slowly add 19.4g of cumene hydroperoxide (80%), keep it warm for 4hrs, detect the reaction solution by TLC until the reaction is complete, and use 960g of 10% sodium hydroxide aqueous solution ( NaOH (96g) was extracted (320g×3), the alkaline aqueous layer was combined, an appropriate amount of dichloromethane was added, and the pH was adjusted to 7~8 with dilute hydrochloric acid. Extract with dichloromethane, combine the organic layers, wash once with saturated brine, add anhydrous sodium sulfate ...

Embodiment 3

[0062] 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylmercapto]-1 H -The preparation of benzimidazole (III)

[0063] Add 10 g of the compound represented by formula VII and 30 g of toluene to the three-necked flask, maintain 95~110 ° C for 15 hours, and detect the reaction solution by TLC until the reaction is complete to obtain 2-chloromethyl-4-hydroxy-3,5-dimethyl base pyridine (VI) reaction solution. Cool down to room temperature, add 10g of phosphorus oxychloride, maintain 110~115°C for 3hrs, detect the reaction solution with thin layer until the reaction is complete, cool down, slowly add 50g of water, add 100g of methanol, slowly add 80g of 15% KOH aqueous solution (KOH is 12 g), after adding, slowly add 8.1 g of 2-mercapto-5-methoxybenzimidazole (IV), raise the temperature to 55°C and react for 2.5 hrs, detect the reaction liquid by TLC until the reaction is complete, add water to wash the reaction liquid, and divide Layers and liquid separation, and the organic ...

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Abstract

The invention discloses a method for preparing an esomeprazole impurity. 5-methoxy-2-[(S)-[(4-chloro-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (II) is obtained through demethylation, halogenation, condensation and asymmetric oxidation by taking 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride as a starting raw material. According to the method disclosed by the invention,a synthesis route is simple and short, the starting raw material is easy to obtain, the reaction conditions are gentle, the operation is simple and convenient, and the impurity can be obtained withoutcolumn chromatography; the purity of the prepared impurity can be up to 99 percent or above, the ee (Enantiomeric Excess) value can be up to 99 percent or above, and the impurity can be used as reference substance in quality research.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a method for preparing esomeprazole impurities. Background technique [0002] Esomeprazole is the world's first isomer proton pump inhibitor (I-PPI) separated and synthesized by AstraZeneca, which was first launched in the UK in September 2000. It is the S-isomer of omeprazole . Its mechanism of action is to reduce gastric acid secretion through a specific targeting mechanism. It is a specific inhibitor of the proton pump in the parietal cells and is weakly alkaline. It is concentrated and converted into The active form, thereby inhibiting the H / K-ATPase (proton pump) at this site, inhibits both basal and stimulated gastric acid secretion. The treatment of gastroesophageal reflux disease is better than omeprazole in terms of symptom relief, gastric acid suppression, and improvement of esophagitis. [0003] The chemical name of esomeprazole is 5-methoxy-2-[( S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 孔祥辉覃志俊周爱新焦慎超张志新
Owner 珠海润都制药股份有限公司
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