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Esomeprazole sodium refining method

A technology of esomeprazole sodium and a refining method, which is applied in the field of chemical medicine, can solve problems such as low optical purity, unqualified appearance and clarity, low optical purity of product purity, etc., and achieve easy industrial production and simple operation Effect

Inactive Publication Date: 2013-12-04
SHANHE PHARMA GUANGZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of its chemical synthesis adopts the method of asymmetric oxidation of prochiral compound-thioether, but the purity of the product obtained by this method is not high, especially the optical purity
Document Tetrahedron: Asymmetry 11 (2000) 3819-3825 reported the synthesis method of esomeprazole sodium by asymmetric oxidation, but its present industry is mainly based on the synthetic method described in this document, starting from the prochiral compound-sulfide, Prepare esomeprazole sodium crude product through asymmetric oxidation reaction, but, this document does not further disclose the refining method of esomeprazole sodium, also does not see the report of relevant esomeprazole sodium refining method in the industry
The optical purity of the product synthesized by the above-mentioned documents is not high, only 92%, which cannot meet the requirements of medicine, and the appearance and clarity are also unqualified, so it must be refined

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] 1. first refining

[0019] Add 10 g of crude esomeprazole sodium that has been synthesized into a 500 ml three-neck flask, dissolve it with 40 ml of acetone, and filter out the insoluble matter. Put 120ml of acetonitrile in the dropping funnel and start mechanical stirring. Acetonitrile was added dropwise. The precipitated solid was filtered and dried under reduced pressure (vacuum degree -0.08Mp, room temperature) for 2 hours to obtain 9.5g, yield 95%. Optical purity 99.0%, content 99.1% (potential titration).

[0020] 2. Second refining

[0021] Add 9.5 g of esomeprazole sodium refined for the first time into a 200 ml three-necked flask, heat to 70°C with 95 ml of methanol to dissolve, and filter out insoluble matter. The filtrate was cooled to -5-0°C, and the precipitated solid was filtered. After vacuum drying (vacuum degree -0.08Mp, room temperature) for 2 hours, 9 g was obtained, and the yield was 95%. Optical purity 99.8% (HPLC chiral column), content 99.5...

Embodiment 2

[0024] 1. First refining

[0025] Add 100 g of crude esomeprazole sodium that has been synthesized into a 5 L three-necked flask, dissolve it with 400 ml of methyl ethyl ketone, and filter out the insoluble matter. Put 1200ml of acetonitrile in the dropping funnel and start mechanical stirring. Acetonitrile was added dropwise. The precipitated solid was filtered and dried under reduced pressure (vacuum degree -0.08Mp, room temperature) for 2 hours to obtain 96g, yield 96%. Optical purity 99.0% (HPLC chiral column), content 99.1% (potentiometric titration).

[0026] 2. Second refining

[0027] Add 96g of esomeprazole sodium refined for the first time into a 2L three-neck flask, heat to 65°C with 960ml of ethanol to dissolve, and filter out the insoluble matter. The filtrate was cooled to -5-0°C, and the precipitated solid was filtered. After vacuum drying under reduced pressure (vacuum degree -0.08Mp, room temperature) for 2 hours, 91 g was obtained, and the yield was 96%....

Embodiment 3

[0030] 1. First refining

[0031] Add 100 g of the synthesized crude esomeprazole sodium into a 5 L three-necked flask, dissolve it with 420 ml of methyl propyl ketone, and filter out the insoluble matter. Put 1210ml of acetonitrile in the dropping funnel and start mechanical stirring. Acetonitrile was added dropwise. The precipitated solid was filtered and dried under vacuum (vacuum degree -0.08Mp, room temperature) for 2 hours to obtain 95g, yield 95%. Optical purity 99.1% (HPLC chiral column), content 99.0% (potential titration).

[0032] 2. Second refining

[0033] Add 95g of esomeprazole sodium refined for the first time into a 2L three-necked flask, heat to 72°C with 950ml of propanol to dissolve, and filter out the insoluble matter. The filtrate was cooled to -5-0°C, and the precipitated solid was filtered. After vacuum drying under reduced pressure (vacuum degree -0.08Mp, room temperature) for 2 hours, 92g was obtained, and the yield was 97%. Optical purity 99.9%...

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Abstract

The invention relates to an esomeprazole sodium refining method. The esomeprazole sodium refining method provided by the invention is used in the refining of an esomeprazole sodium crude product synthesized from a prochiral compound sulfide through an asymmetric oxidation reaction. The refining method comprises the steps that: the esomeprazole sodium crude product synthesized through the asymmetric oxidation reaction is adopted as a raw material, and is dissolved by using low-grade organic ketone; acetonitrile is added; after crystallization and precipitation, filtering is carried out, such that a refined product after first crystallization is obtained; the refined product is subjected to heating and dissolving by using low-grade organic alcohol; the mixture is cooled; and after crystallization and precipitation, filtering is carried out, such that a refined product after second crystallization is obtained. Optical purity of the esomeprazole sodium refined product is improved from 92% of the crude product to higher than 99.8%, and content is higher than 99.5%.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and relates to a method for refining esomeprazole sodium, a raw material drug of proton pump inhibitors. Background technique [0002] Esomeprazole is the world's first isomeric proton pump inhibitor, which reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells. As a new generation of proton pump inhibitors, esomeprazole sodium has the advantages of fast absorption and few side effects. Most of its chemical synthesis adopts the method of asymmetric oxidation of prochiral compound-thioether, but the purity of the product obtained by this method is not high, especially the optical purity. Document Tetrahedron: Asymmetry 11 (2000) 3819-3825 reported the synthesis method of esomeprazole sodium by asymmetric oxidation, but its present industry is mainly based on the synthetic method described in this document, starting from the prochiral compound-sulfide,...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 苏军王景成
Owner SHANHE PHARMA GUANGZHOU CITY
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