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Industrial production method of high-purity esomeprazole sodium

A technology for esomeprazole sodium and a production method is applied in the field of high-purity esomeprazole sodium, can solve the problems of taking a long time, cannot be separated, and is difficult to industrially scale up production, and achieves high economic value and social benefit. , The oxidation reaction time is short, and the effect of reducing gastric acid secretion

Active Publication Date: 2012-01-18
NANJING HAIRUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Due to the use of liquid reaction materials such as organic bases in the prior art, they cannot be separated from the reaction liquid immediately after the reaction. During post-treatment, insoluble substances are precipitated from time to time, which affects the operation. For a long time; as we all know, omeprazole solution has poor stability, and it is easily catalyzed and oxidized by oxygen and light to form sulfone impurities during the storage process, resulting in dark color of the final product, high related substances, and low purity, which cannot reach the pharmaceutical grade. Require
The prior art process has poor repeatability, takes a long time, and is not easy for industrial scale-up production

Method used

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  • Industrial production method of high-purity esomeprazole sodium
  • Industrial production method of high-purity esomeprazole sodium
  • Industrial production method of high-purity esomeprazole sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of esomeprazole sodium

[0049] Add 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole 16g (48.6mmol) and 100mL (86.6g) toluene, stir to dissolve, add 0.15mL (8.1mmol) of water, 10g (48.6mmol) of D-diethyl tartrate and 6.9g (24.3mmol) of titanium isopropoxide, and keep the reaction at 50°C for about 1h. Add potassium carbonate 3.35g (24.3mmol), cool to 20°C, add cumene hydroperoxide 8.7g (content 85%, 48.6mmol), react at 20°C and monitor the reaction liquid by HPLC, react for about 2 hours, raw material 5 -Methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole basic reaction is completed (less than 2% raw material);

[0050] Add 20ml of methanol (15.8g) to the above reaction solution, stir for 10 minutes, filter the insoluble matter, add ammonia water to the filtrate to extract the organic layer (60ml*4), adjust the pH of the obtained ammonia solution to about 8 with acetic acid, and use ethyl acetate Extracted, then...

Embodiment 2

[0055] Preparation of esomeprazole sodium

[0056] Add 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole 500g (1.52mol) and 4.5 kg toluene, stir to dissolve, add water 5.5mL (0.31mol), D-diethyl tartrate 313g (1.52mol) and titanium isopropoxide 217.5g (0.76mol), keep the reaction at 50°C for about 1h, add potassium carbonate 4.2g (0.03mol), cooled to 5°C, added cumene hydroperoxide 272g (content 85%, 1.52mol), reacted at 5°C and monitored the reaction liquid by HPLC, reacted for about 2 hours, raw material 5-methoxy -2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole basic reaction is completed (less than 2% raw material);

[0057] Add 475ml (375g) of methanol to the above reaction solution, stir for 15 minutes, filter the insoluble matter, add ammonia water to the filtrate to extract the organic layer (2000ml*4), adjust the pH of the obtained ammonia solution to about 7.5 with acetic acid, and extract with ethyl acetate , and then dried,...

Embodiment 3

[0062] Preparation of esomeprazole sodium (with reference to Chinese patent CN1070489)

[0063] Add 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole 500g (1.52mol) and 4L to the reaction flask Heat toluene to 54°C, stir to dissolve, add 3.55mL (0.2mol) of water, 190g (0.92mol) of D-diethyl tartrate and 129g (0.45mol) of titanium isopropoxide, and keep the reaction at 54°C for about 50 minutes , cooled to 10°C, and then 58g (0.45mol) of diisopropylethylamine was added to the solution, 272g (content 85%, 1.52mol) of cumene hydroperoxide was added, and the reaction was monitored by HPLC at 10°C. React about 3 hours, raw material 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole basic reaction finishes (raw material 2 %the following);

[0064] Add ammonia water to the above reaction solution to extract the organic layer (1600ml*3), add 2000ml methyl isobutyl ketone to the obtained ammonia solution, adjust the pH to ...

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Abstract

The invention relates to an industrial production method of high-purity esomeprazole sodium. The industrial production method is characterized by comprising the following steps: mixing a raw material 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole with a solvent for dissolving 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole; and successively adding water, D-diethyl tartrate and titanium iso-propoxide as well as an inorganic base, then adding cumene hydroperoxide, adding methanol or ethanol after reaction, filtering, carrying out posttreatment and salifying to prepare high-purity esomeprazole sodium, wherein the inorganic base is one of potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. By using the method in the invention, the defects of high cost and serious environment pollution which are caused by using the organic base in the prior art are solved, and the defects of difficult posttreatment, poor repeatability and difficult industrialization in the prior art are solved simultaneously. According to the invention, the inorganic base is used as the raw material, thus the industrial production method has the advantages of low cost, little environment pollution, short reaction time and high product purity, is easy to operate and industrially produce.

Description

technical field [0001] What the present invention relates to is a kind of industrialized production method of high-purity esomeprazole sodium. Background technique [0002] The chemical name of esomeprazole sodium is 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl- 1H-benzimidazole sodium; [0003] Structural formula: [0004] [0005] Molecular formula: C 17 h 20 N 3 NaO 3 S [0006] Molecular weight: 369.41. [0007] Esomeprazole sodium (trade name: I.V.) is the S-optical isomer of omeprazole sodium, the world's first isomer proton pump inhibitor (PPI), which reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells. Esomeprazole was developed by AstraZeneca. It was approved by the FDA for the first time in 1999. It was approved by the European Union in March 2000. It was approved in China in 2002 and launched nationwide in 2003. Esomeprazole sodium for injection was approved by the FDA on March 31...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 赵俊宗在伟杜有国王易刘文杰
Owner NANJING HAIRUN PHARM CO LTD
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