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Method for synthesizing esomeprazole sodium

A technology for esomeprazole sodium and a production method is applied in the field of drug synthesis, can solve the problems of high raw material cost, harsh operating conditions, low purity and the like, and achieves the effects of reducing production cost, easily controlling temperature, and simplifying operation steps

Active Publication Date: 2013-04-17
KAMP PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the existing synthetic route, there are defects such as high cost of raw materials, high toxicity of raw materials, and harsh operating conditions.
Due to the poor stability of esomeprazole, it is easily catalyzed and oxidized by oxygen, light, etc. after being left for a long time, so the yield is low and the purity is low, which cannot meet the requirements of pharmaceutical grade, and the reaction time is long, so it is not easy for industrial scale-up production

Method used

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  • Method for synthesizing esomeprazole sodium
  • Method for synthesizing esomeprazole sodium
  • Method for synthesizing esomeprazole sodium

Examples

Experimental program
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Embodiment 1

[0054] Reduce to 25°C for suction filtration, and the filtrate (red-brown) was evaporated under reduced pressure at 45°C to remove about 1 / 2 of the methanol (with solid precipitation), and then extracted with 12L of water and 12L of dichloromethane (boiling point 39.8). The aqueous layer was extracted once more with 8 L of dichloromethane. The combined dichloromethane layers were washed with 5 L of water and 5 L of saturated brine, dried with 2000 g of anhydrous sodium sulfate for 2 hours, filtered with suction, and the filter cake was washed with dichloromethane. Dichloromethane was distilled off under reduced pressure to obtain an oil. Heat the oily product with 10L of acetonitrile (boiling point 81.1°C) at 85°C for 30 minutes, then cool and stir to crystallize naturally (overnight, at least 3.5 hours), then suction filter (centrifugal filtration), wash the filter cake (filter residue) with 2L of acetonitrile, vacuum (drum) at 30°C wind) drying (over 4 hours) to obtain 38...

Embodiment 2

[0063] Add 1568g esomeprazole intermediate (5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H- in 20L reactor benzimidazole), then slowly stirred and dissolved with 6.4L toluene, and then added 600g D-(-) diethyl tartrate after heating up to 50°C-55°C, then added 40ml purified water and stirred for 0.5 hours, then added 410g titanium isopropoxide , continue stirring for 50min. Cool down to 25±2°C, add 190g of diisopropylamine and stir for 5min, add dropwise 820g of cumene hydroperoxide with a mass concentration of 80% (the temperature is controlled at 25±2°C during the dropwise addition). After the dropping, stir and react at 25±2°C for 3 hours, and check by TLC every hour. After the reaction was completed, 3 L of concentrated ammonia water and 3 L of purified water were added to the reaction liquid, stirred for 30 min, and then the ammonia water layer was extracted. The reaction solution was then extracted once with 3L of concentrated ammonia water and 3L of puri...

Embodiment 3

[0065] Add 1568g esomeprazole intermediate (5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H- in 20L reactor benzimidazole), then slowly stirred and dissolved with 6.4L toluene, and then added 600g D-(-) diethyl tartrate after heating up to 50°C-55°C, then added 40ml purified water and stirred for 0.5 hours, then added 410g titanium isopropoxide , continue stirring for 50min. Cool down to 20°C, add 190g of diisopropylamine and stir for 5 minutes, then add 820g of cumene hydroperoxide with a mass concentration of 80% dropwise (the temperature is controlled at 20±2°C during the dropwise addition). After dropping, stir and react at 20±2°C for 5 hours. After the reaction was completed, 1362.3 g of the crude product was obtained after extraction, salt formation, concentration, washing, and vacuum drying, with a yield of 77.2% and an enantiomeric purity of 99.3%.

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Abstract

The invention discloses a method for synthesizing esomeprazole sodium. The method comprises the steps as follows: preparing 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole, namely prochirality thioether; preparing crude esomeprazole sodium; refining the crude esomeprazole sodium; adding the prepared prochirality thioether and dried methylbenzene into D-(-) diethyl tartrate and water by stirring, adding titanium isopropylate, and stirring; and adding diisopropylamine at constant temperature, stirring, dropwise adding cumyl hydroperoxide with the mass concentration of 80%, ending the reaction, extracting, salifying, concentrating, washing and carrying out vacuum drying to obtain a crude product, and refining the crude product to obtain the esomeprazole sodium. The method is low in cost, toxicity and pollution, easy to operate, short in reaction time, high in product purity and easy for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis and production method of esomeprazole sodium. Background technique [0002] Omeprazole is a new type of proton pump inhibitor anti-ulcer drug listed by Astra Pharmaceutical Company of Sweden in 1988. Omeprazole is a 1:1 ratio of two optical isomers, R-type and S-type. mixture, and its S optical isomer, namely S-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl ]}-1H-benzimidazole is esomeprazole. [0003] The structural formula of esomeprazole sodium is as follows: [0004] [0005] Molecular formula: C 17 h 18 N 3 NaO 3 S, molecular weight: 367.4. [0006] Esomeprazole sodium is the world's first isomer proton pump inhibitor (PPI), which reduces gastric acid secretion through a specific targeting mechanism and is a specific inhibitor of proton pumps in parietal cells. The new generation of PPI esomeprazole sodium for injection has unique pharmac...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 曾培安吴锋刘栋华张浩吴建明张静贺莲刘娟
Owner KAMP PHARMA
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