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Preparation method of esomeprazole sodium

A technology of esomeprazole sodium and omeprazole, which is applied in the preparation field of preparation methods, can solve the problems of unsuitability for large-scale industrial production, dark color of inclusion complexes, and great toxicity to human body, and achieve appearance quality Good, good quality, less environmental pollution effect

Active Publication Date: 2014-12-10
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This method uses toluene, xylene as solvent in the preparation of esomeprazole and (S)-(-)-[1,1'-binaphthalene]-2,2'-diphenol inclusion complex, because The reaction temperature is high, the dark color of the prepared inclusion complex needs to be washed with a large amount of toluene, and the operation is very harmful to the human body; multiple extractions are required during the preparation of magnesium salts, and rotary evaporation is not suitable for industrialized large-scale production

Method used

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  • Preparation method of esomeprazole sodium
  • Preparation method of esomeprazole sodium

Examples

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Effect test

Embodiment 1

[0037] Example 1 Preparation of esomeprazole and (S)-(-)-[1,1'-binaphthyl]-2,2'-diphenol inclusion complex (IV).

[0038] In a 20L reactor, add racemic omeprazole 3.0kg (8.685mol), (S)-(-)-[1,1'-binaphthyl]-2,2'-diphenol 1.492kg (5.211mol), triethylamine 0.879kg (8.685mol) and absolute ethanol 12L, heat to 75°C and heat-preserve to dissolve, after dissolving, heat-preserve and stir at 60°C for 2h; cool to 30°C to crystallize, filter the suspended solid, filter cake After washing with 6L of ethanol and vacuum drying at 50°C, 2.442kg of off-white solid was obtained. Yield: 89%, HPLC purity (normalized method): 98.69%, optical purity (e.e%): 99.43%.

Embodiment 2

[0039] Example 2 Preparation of esomeprazole and (S)-(-)-[1,1'-binaphthyl]-2,2'-diphenol inclusion complex (IV).

[0040] In a 50L reactor, add racemic omeprazole 5.0kg (14.475mol), (S)-(-)-[1,1'-binaphthyl]-2,2'-diphenol 2.488kg (8.685mol), triethylamine 1.465kg (14.475mol) and 2-propanol 25L, heat to 70°C and heat-preserve to dissolve, after dissolving, keep stirring at 55°C for 3 hours; cool to 35°C for crystallization, filter the suspended solid, and filter The cake was washed with 10 L of 2-propanol and dried under vacuum at 50°C to obtain 4.001 kg of off-white solid. Yield: 87.5%, HPLC purity (normalized method): 98.34%, optical purity (e.e.%): 99.55%.

Embodiment 3

[0042] In a 50L reactor, add racemic omeprazole 5.0kg (14.475mol), (S)-(-)-[1,1'-binaphthyl]-2,2'-diphenol 2.07kg (7.2375mol), 4.3425mol of diethylamine and 15L of methanol, heated to 65°C and kept to dissolve, then stirred at 50°C for 2h after dissolving; cooled to 40°C for crystallization, filtered the suspended solid, washed the filter cake with 10L of methanol and placed in After vacuum drying at 50°C, 4.0 kg of off-white solid was obtained. Yield: 87.9%, HPLC purity (normalized method): 98.36%, optical purity (e.e%): 99.32%.

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Abstract

The invention provides a preparation method of esomeprazole sodium. The preparation method comprises steps as follows: 1, heating omeprazole and (S)-(-)-(1, 1'-dinaphthalene)-2, 2'-diphenol to reach 65-75 DEG C and dissolving into a solvent A, lowering temperature and reacting by heat preservation in the presence of weak base, and cooling and crystallizing, so as to obtain inclusion complex; and 2, heating the inclusion complex and sodium hydroxide and dissolving into an organic solvent B, and heating and reacting by heat preservation, then adding an organic solvent C, cooling to reach 0-15 DEG C to crystallize, and finally filtering, so as to obtain the esomeprazole sodium; or heating the inclusion complex and sodium hydroxide and dissolving into a mixture of the organic solvent B and the organic solvent C, and heating and reacting by heat preservation, then cooling to crystallize, and finally filtering to obtain the esomeprazole sodium. The preparation method of the esomeprazole sodium provided by the invention is simple and convenient in technology, high in purity of products, high in quality, high in yield, less in environmental pollution and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of esomeprazole sodium. Background technique [0002] Omeprazole (Omeprazole, trade name Losec) is developed by Astra Company in Sweden. It is the world's first clinically applied proton pump inhibitor (PPI) for the treatment of gastric ulcer, duodenal ulcer and reflux esophagus. A cure for inflammatory ulcers. [0003] Esomeprazole, chemical name 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl- 1H-benzimidazole, the S-optical isomer of omeprazole, is the world's first isomer proton pump inhibitor, which reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells. Esomeprazole sodium is The sodium salt of esomeprazole, its structural formula is: [0004] [0005] At present, existing patent documents disclose methods for obtaining enantiomer S-omeprazole and salts thereof by resol...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 朱永强杨杨李洪阳朱勇
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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