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Preparing method for esomeprazole magnesium

A technology for esomeprazole magnesium and crude esomeprazole magnesium is applied in the field of chemical drug synthesis, can solve the problems of excessive residual solubility, large loss, complicated operation and the like, and achieves controllable cost, mild reaction, and easy operation. simple effect

Inactive Publication Date: 2016-01-06
ZHEJIANG DAVI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Step 1 uses omeprazole as a starting material to split to obtain esomeprazole; in the split process, a benzene solvent is used, which is highly toxic and the residual solvent exceeds the standard; further purification of esomeprazole is required, The operation is cumbersome, the loss is large, and the yield is low
Step 2 is that esomeprazole reacts to generate esomeprazole potassium salt, and reacts with inorganic magnesium salt to obtain esomeprazole magnesium after the potassium salt is filtered, causes the yield of final product to be lower, is not suitable for industrial scale production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of omemersulfide, the specific operation is as follows:

[0031] Add sodium hydroxide solution with a solubility of 70% to methanol, stir evenly, add 2-mercapto-5-methoxybenzimidazole while stirring, and then continue to add 2-chloromethyl-3,5-di Methyl-4-methoxypyridine hydrochloride, raise the temperature of the mixed solution to 86°C, keep it warm for 2.5h, when the temperature drops to 22°C, concentrate under reduced pressure, add dichloromethane, extract, wash with water, and recover dichloromethane After methane, add ethyl acetate, stir and crystallize at 18°C ​​for 4.5h, centrifuge, and dry at 47°C to obtain omethioether;

[0032] (2) The obtained omeprazole is oxidized under the action of phthalic anhydride and an oxidizing agent to obtain omeprazole, and the specific operation is as follows:

[0033] Add omemersulfide into dichloromethane, stir evenly, then add phthalic anhydride, lower the temperature to 32°C, then add sodium carbonate, keep war...

Embodiment 2

[0039] (1) Synthesis of omemersulfide, the specific operation is as follows:

[0040] Add sodium hydroxide solution with a solubility of 80% to methanol, stir evenly, add 2-mercapto-5-methoxybenzimidazole while stirring, and then continue to add 2-chloromethyl-3,5-di For methyl-4-methoxypyridine hydrochloride, raise the temperature of the mixed solution to 90°C and keep it warm for 2-3h. When the temperature drops to 25°C, concentrate under reduced pressure, add dichloromethane, extract, wash with water, and recover di After methyl chloride, ethyl acetate was added, stirred and crystallized at 20°C for 5h, centrifuged, and dried at 50°C to obtain omethioether;

[0041] (2) The obtained omeprazole is oxidized under the action of phthalic anhydride and an oxidizing agent to obtain omeprazole, and the specific operation is as follows:

[0042] Add omemersulfide into dichloromethane, stir evenly, then add phthalic anhydride, lower the temperature to 35°C, then add sodium carbonat...

Embodiment 3

[0048] (1) Synthesis of omemersulfide, the specific operation is as follows:

[0049] Add methanol to the reaction kettle, add sodium hydroxide solution with a solubility of 60% to the methanol, stir evenly, add 2-mercapto-5-methoxybenzimidazole while stirring, and then continue to add 2-chloroform Base-3,5-dimethyl-4-methoxypyridine hydrochloride, raise the temperature of the mixed solution to 85°C, keep it warm for 2h, when the temperature drops to 20°C, concentrate under reduced pressure, add dichloromethane, extract , washing with water, and recovering dichloromethane, adding ethyl acetate, stirring and crystallizing at 15°C for 4h, centrifuging, and drying at 45°C to obtain omemersulfide;

[0050] (2) The obtained omeprazole is oxidized under the action of phthalic anhydride and an oxidizing agent to obtain omeprazole, and the specific operation is as follows:

[0051] Add omemersulfide into dichloromethane, stir evenly, then add phthalic anhydride, lower the temperature...

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Abstract

The invention relates to a preparing method for esomeprazole magnesium. The method comprises esomeprazole magnesium crude product manufacturing steps that 1, omeprazole thioether is synthesized; 2, obtained omeprazole thioether is oxidized under the effects of phthalic anhydride and oxidizing agents to obtain omeprazole, and omeprazole is salinized in a sodium mode to obtain omeprazole sodium; 3, omeprazole sodium is complexed to obtain an omeprazole sodium complex; 4, solvent A,N,N-diethyl ethylamine and 1-phenol acetic acid are added into the omeprazole sodium complex, and the mixture reacts to obtain an esomeprazole sodium complex; 5, alkali, solvent B and purified water are added into the esomeprazole sodium complex, the mixture is stirred for two hours and layered, after an alkaline water layer is acidized, the solvent B is used for extraction, and the mixture is dried and evaporated to dryness in a pressure reducing mode to obtain an esomeprazole magnesium crude product. According to the preparing method, the reaction is mild, the yield is high, and the requirement of esomeprazole magnesium serving as a crude drug can be met; no toxic reagent is needed, and environmental friendliness is achieved; operation is easy, reagents participating in the reaction are common reagents, and cost is controllable.

Description

technical field [0001] The invention belongs to the synthetic field of chemical medicines, and relates to a preparation method of esomeprazole salt, in particular to a preparation method of esomeprazole magnesium. Background technique [0002] Esomeprazole has improved pharmacokinetic properties and improved therapeutic effects such as lower inter-individual variability. Esomeprazole magnesium is the magnesium salt form of esomeprazole, a well-known gastric ion pump inhibitor. [0003] In the prior art, esomeprazole magnesium trihydrate is prepared by resolution, such as a method for preparing esomeprazole magnesium trihydrate disclosed in a Chinese invention patent of CN104447699, mainly comprising Two key steps. Step 1 uses omeprazole as a starting material to split to obtain esomeprazole; in the split process, a benzene solvent is used, which is highly toxic and the residual solvent exceeds the standard; further purification of esomeprazole is required, The operation i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 任永辉柴志善夏兴进何龙丹
Owner ZHEJIANG DAVI PHARMA
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