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High-purity esomeprazole sodium preparation method

A technology for esomeprazole sodium and esomeprazole is applied in the field of preparation of high-purity esomeprazole sodium, can solve problems such as being unsuitable for industrial production, high equipment requirements, and many product impurities, and achieves operation Simple, reproducible, high product yield and purity

Inactive Publication Date: 2016-11-09
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Chinese patent application CN94190335.4 discloses the method for preparing esomeprazole sodium by esomeprazole in sodium hydroxide aqueous solution, methyl ethyl ketone, toluene, and the product impurity that this method prepares gained is more, and yield is lower
[0005] Chinese patent application CN201110203200.3 discloses the method for preparing esomeprazole sodium by esomeprazole oily substance in sodium hydroxide aqueous solution, acetonitrile or acetone, and this method needs to carry out crystallization under low temperature condition and yield is relatively high. Low, not suitable for industrial production
[0007] Chinese patent application CN201210197734.4 discloses a preparation method of nano-esomeprazole sodium. The salt formation and crystallization of this method are carried out in an ultrasonic microwave chemical reactor, which requires high equipment and is not suitable for industrial production.
[0013] The main impurity that exists in esomeprazole sodium is the peroxide impurity of formula I, and this impurity is similar to product structure, and property is similar, and is difficult to remove

Method used

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Experimental program
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Effect test

Embodiment 1

[0051] The preparation of embodiment 1 esomeprazole sodium

[0052] Dissolve 100g of esomeprazole in 1800ml of acetonitrile and 200ml of methyl isobutyl ketone, and stir at 10°C until dissolved. Add 69.5ml of sodium hydroxide aqueous solution (13.9g of sodium hydroxide dissolved in 55.6ml of water) dropwise, control the drop rate, and finish dropping in 20 minutes. After dropping, stir and crystallize at 10°C for 8 hours. After filtering, the filter cake was stirred and washed twice with a mixed solvent of acetone / methyl tert-butyl ether (v / v=1 / 1), each time 200 ml, each time 10 minutes. After filtering, the filter cake was vacuum-dried at 40° C. to obtain 85 g of white solid, with a molar yield of 85%, a chromatographic purity of 99.92%, an optical purity of 99.89%, and a formula I peroxidation impurity content of 0.01%.

Embodiment 2

[0053] The preparation of embodiment 2 esomeprazole sodium

[0054] Dissolve 100g of esomeprazole in 3429ml of tetrahydrofuran and 571ml of acetone, and stir at 20°C until dissolved. 29ml of aqueous sodium hydroxide solution (11.6g of sodium hydroxide dissolved in 17.4ml of water) was added dropwise, the dropping speed was controlled, and the dropping was completed in 40 minutes. After the dropping, stirred and crystallized at 20°C for 9 hours. After filtering, the filter cake was stirred and washed twice with a mixed solvent of acetone / ether (v / v=1 / 3), each time 400 ml, each time 20 minutes. After filtration, the filter cake was vacuum-dried at 45° C. to obtain 87 g of a white solid with a molar yield of 87%, a chromatographic purity of 99.93%, and an optical purity of 99.91%. The peroxidized impurities of formula I were not detected.

Embodiment 3

[0055] The preparation of embodiment 3 esomeprazole sodium

[0056] Dissolve 100g of esomeprazole in 5455ml of dichloromethane and 545ml of butanone, and stir at 30°C until dissolved. 38.7ml of sodium hydroxide aqueous solution (23.2g of sodium hydroxide dissolved in 15.5ml of water) was added dropwise, the drop rate was controlled, and the drop was completed in 60 minutes. After the drop, stirred and crystallized at 30°C for 10 hours. Filter, and the filter cake is stirred and washed 4 times with a mixed solvent of acetone / n-heptane (v / v=1 / 5), each dosage is 600ml, and each time is 30 minutes. After filtration, the filter cake was vacuum-dried at 50° C. to obtain 84 g of a white solid with a molar yield of 84%, a chromatographic purity of 99.94%, an optical purity of 99.92%, and no peroxidized impurities of formula I were detected.

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Abstract

The invention discloses a high-purity esomeprazole sodium preparation method. The method comprises the following steps: A) dissolving esomeprazole sodium in a mixed solvent of an organic solvent A and an organic solvent B; B) dropping a sodium hydroxide aqueous solution, stirring the materials for crystallization; C) filtering the material, stirring a filter cake by a mixed solvent of acetone and an organic solvent C and washing the filter cake; and D) filtering the material, and performing vacuum drying on the filter cake to obtain the product. The method has the advantages of good repeatability, simple operation, high products yield, and high purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of high-purity esomeprazole sodium. Background technique [0002] Esomeprazole Sodium (Esomeprazole Sodium), the chemical name is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl ]sulfinyl]-1H-benzimidazole sodium. Esomeprazole is a class of proton pump inhibitors (proton pump inhibitors, PPIs) developed by AstraZeneca. It is the S isomer of omeprazole, which reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells. In recent years, the drug has been at the forefront of the world's best-selling drugs and has broad market prospects. The chemical structural formula of esomeprazole sodium is as follows: [0003] [0004] Chinese patent application CN94190335.4 discloses the method for preparing esomeprazole sodium by esomeprazole in aqueous sodium hydroxide solution, butanone, and toluene, and the produ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 袁峰泉陈杨杨金荣庆宣景安陈令武刘文东
Owner YANGTZE RIVER PHARM GRP CO LTD
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