Industrial production method of esomeprazole

Abstract

The invention provides an industrial production method of esomeprazole. According to the industrial production method, under the action of a phase transfer catalyst and strong alkali, omeprazole sulfur ether is prepared through condensation; through low-temperature asymmetric oxidation, the generation of nitric oxide and sulfone is reduced, an organic solution of esomeprazole (as shown in the formula III) is prepared, the organic solution can be directly fed into a sodium alcoholate solution, three steps namely asymmetric oxidation aftertreatment, salting and crystallization and refining are completed once, a finished esomeprazole product is prepared in multiple batches, the purity of the finished esomeprazole product is greater than 99.8%, the isomer of the finished esomeprazole product is less than 0.05%, the individual impurity of the finished esomeprazole product is less than 0.1%, and the medicine grade raw material medicine requirements are met. By adopting the preparation method, the step of extracting and purifying esomeprazole and esomeprazole sodium is canceled, the production period is shortened, the production cost is greatly reduced, the possibility that the sulfone impurity is increased in the production process is avoided, the preparation method is safe and reliable, simple and easy to operate, stable in salting and good in repeatability, and the product quality is greatly improved.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, in particular to an industrial production method of esomeprazole sodium. Background technique [0002] Esomeprazole sodium is a commonly used anti-ulcer drug, which was successfully developed by AstraZeneca in Sweden for the first time. It is the world's first isomer proton pump inhibitor (PPI) and is used for the treatment of peptic ulcer and gastroesophageal reflux disease. , (GERD), the drug of choice for acid-related diseases such as duodenal ulcer. Esomeprazole sodium reduces gastric acid secretion through a specific targeting mechanism. It is a specific inhibitor of proton pumps in parietal cells. Because of its definite curative effect, it has successfully replaced omeprazole and has become the first-line anti-ulcer heavyweight drug. [0003] [0004] CN102633776B and CN103601723A processes directly add excess sodium hydroxide solution to the reaction solution of ...

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Problems solved by technology

[0004] CN102633776B and CN103601723A processes directly add excess sodium hydroxide solution to the reaction solution of step (2) asymmetric oxidation, which destroys the complex stable structure of tetraisopropyl titanate and D-ethyl tartrate, resulting in the oxidation of titanium The generation of fine particles is easy to form emulsification, which makes it difficult to stratify. CN102633776B and CN103288801A esomeprazole (compound represented by formula III) sulfoxide has poor stability, especially in an acidic atmosphere, it is very easy to oxidize and change color, and sulfoxide is oxidized to sulfone , while concentrating for a long time tends to cause the sulfone impurity (compound shown in formula IV) to become larger

CN103936715A The solvent of omeprazole thioether selects hydrophilic alcohols, reflux operation, and the reaction temperature is higher. At the same time, it n

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