Preparation method of esomeprazole sodium

A technology of esomeprazole sodium and a benign solvent, which is applied in the field of preparation of esomeprazole sodium, can solve problems such as low yield and difficult solvent recovery, and achieve high yield, improved operability, and high purity Effect

Inactive Publication Date: 2015-04-29
JIANGSU ZHONGBANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The invention provides a preparation method of esomeprazole sodium using a single solvent, and achieves the purpose of improving the crystallization yield by controlling the water in the solution system, and solves the problem of using mixed solvents for crystallization and solvent recovery in the prior art. Difficult, lower yield disadvantages

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  • Preparation method of esomeprazole sodium

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preparation example Construction

[0026] Preparation of esomeprazole free acid

[0027] In the present invention, the preparation method of esomeprazole free acid adopts the disclosed general synthetic method of present WO94 / 27988, and the method is as follows:

[0028] 30kg of toluene, 5kg of D-(-)-diethyl tartrate, 40kg of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridine Base) methyl] sulfenyl] -1H-benzimidazole, stir and heat up to 60±, then add 3.0kg tetraisopropyl titanate and 2.2kg N,N-diisopropylethylamine, keep stirring for 30 minutes, Want to add 26kg cumene hydroperoxide dropwise in the still, and react at room temperature for 1 hour after the dropwise addition is completed. Sodium bicarbonate, extracted with 200kg dichloromethane, after the extraction was completed, the dichloromethane layer was dried by adding 5kg anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 32kg brown viscous oil, which was esomeprazole free acid, HPLC The analytical chemical purity is 99...

Embodiment 1

[0030] Preparation of esomeprazole sodium

[0031] Put 5 kg (14.5 mol) of esomeprazole and 25 kg of methanol into the reaction kettle, stir and dissolve at room temperature, slowly add 0.57 kg (14.4 mol) of sodium hydroxide to the kettle, complete the addition, and stir for 0.5 hours to react. After the reaction is completed, the reaction solution is concentrated under reduced pressure at 40°C until the water content is ≤0.15%. After the concentration is completed, a large amount of white solids are precipitated in the kettle, and the temperature in the kettle is slowly reduced to 0±5, stirred for 2 hours, filtered, and vacuum-dried to obtain Exome The finished product of prazole sodium is 4.5kg, and the yield is 84.9%.

Embodiment 2

[0033] Preparation of esomeprazole sodium

[0034] 5kg (14.5mol) esomeprazole, 50kg isopropanol are dropped into reactor, at room temperature, in stirring and dissolving, slowly in kettle, add 0.57kg (14.4mol) sodium hydroxide, add complete, stirring reaction 0.5 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure at 40°C until the water content is ≤0.15%. After the concentration is completed, a large amount of white solids are precipitated in the kettle, and the temperature in the kettle is slowly reduced to 0±5, stirred for 2 hours, filtered, and vacuum-dried to obtain Exome The finished product of prazole sodium is 4.8kg, and the yield is 90.5%.

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Abstract

The invention relates to a preparation method of esomeprazole sodium. The preparation method comprises the following steps: dissolving esomeprazole free acid in a benign solvent in azeotropy with the water, adding sodium hydroxide to form salt, dehydrating through distillation azeotropy to reduce the water content in a solution system to be less than 0.2%, and cooling for crystallizing, thereby obtaining the esomeprazole sodium with high yield. The preparation method is simple in operation, the process yield is greatly promoted, the obtained product has high purity, the excellent single solvent is adopted, and the industrialization can be easily realized.

Description

technical field [0001] The preparation method of the esomeprazole sodium that the present invention relates to. technical background [0002] Esomeprazole Sodium (Esomeprazole Sodium), the chemical name is S-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] Sulfonyl}-1H-benzimidazole sodium. The structural formula is as follows: [0003] [0004] A new generation of proton pump inhibitors developed by AstraZeneca, which was first launched in 1999, is now available in many countries. Esomeprazole, the S-optical isomer of omeprazole, is 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 sodium is the sodium salt of esomeprazole. [0005] Esomeprazole sodium is not easy to recrystallize and the free acid of esomeprazole itself is easily oxidized and unstable, resulting in the solvent used in the salt formation process and the crystallization yi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 钱刚周颖徐强薛谊李维思陈国萍
Owner JIANGSU ZHONGBANG PHARMA
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