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Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol

A technology of inclusion complexes and omeprazole, which is applied in the fields of drug combination, digestive system, organic chemistry, etc. It can solve the problems of unsuitable for industrial production, unsuitable for large-scale production, low optical purity of S-omeprazole, etc. problem, to achieve the effect of high ee value, low environmental pollution and high yield

Active Publication Date: 2012-07-04
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 2. The optical purity of S-omeprazole in the inclusion complex is low, and the product needs to be further purified;
[0011] 3. Use benzene as a solvent, which is a highly toxic solvent and is not suitable for industrial production;
[0012] 4. The resolution agent is removed by chromatography, which is not suitable for large-scale production

Method used

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  • Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol
  • Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of S-omeprazole and (S)-(-)-1,1'-binaphthyl-2,2'-diphenol inclusion complex

[0047]249g (0.87mol) of (S)-(-)-1,1'-binaphthyl-2,2'-diphenol was dissolved in 3L of toluene, and at 80°C, 300g (0.87mol) of azulene was added to the solution. For meprazole, cool to 65°C within 15 minutes after dissolving, add 9g of S-omeprazole and (S)-(-)-1,1'-binaphthyl-2,2'-diphenol inclusion complex Seed crystals, and then lowered to 45°C within 20 minutes, a solid precipitated, filtered, washed with toluene, and dried to obtain off-white crystals. (261.5g, yield 92%, ee value 98.5%)

Embodiment 2

[0048] Example 2: Preparation of S-omeprazole and (S)-(-)-1,1'-binaphthyl-2,2'-diphenol inclusion complex

[0049] 249g (0.87mol) of (S)-(-)-1,1'-binaphthyl-2,2'-diphenol was dissolved in 3L of toluene, and at 70°C, 300g (0.87mol) of azulene was added to the solution. For meprazole, cool to 60°C within 15 minutes after dissolving, add 9g of S-omeprazole and (S)-(-)-1,1'-binaphthyl-2,2'-diphenol inclusion complex Seed crystals, and then lowered to 40°C within 20 minutes, a solid precipitated, filtered, washed with toluene, and dried to obtain off-white crystals. (253g, yield 90%, ee value 98.2%)

Embodiment 3

[0050] Embodiment 3: the preparation of S-omeprazole magnesium salt

[0051] Dissolve 48.6g (0.87mol) of potassium hydroxide in 1.5L of water to form a potassium hydroxide solution, then add 300g (0.485mol) of S-omeprazole and (S)-(-)-1,1' - Binaphthalene-2,2'-diphenol inclusion complex (prepared by the method of Example 1 or 2), add 1.3L of isopropyl acetate, separate the water layer, and then extract the water layer with isopropyl acetate until Remove (S)-(-)-1,1'-binaphthyl-2,2'-diol from the water layer, and add a pre-prepared magnesium chloride aqueous solution (magnesium chloride hexahydrate 93.4g, water 240g) into the water layer , formed a precipitate, was filtered, and the solid was washed with water to obtain 202.6 g of a wet product (the yield on a dry basis was 92%).

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Abstract

The invention provides a method for preparing S-Omeprazole and salt thereof by the resolution of racemic modification Omeprazole by an inclusion resolution method, the resolution regent of the inclusion resolution method is (S)-(-)-1, 1'-binaphthyl-2, 2'-diphenol, by adding S-Omeprazole and S-1, 1'-binaphthyl-2, 2'-diphenol inclusion complex seed grains at the temperature of 60 to 70 DEG C, the inclusion complex is obtained, then the inclusion complex is processed by the hydroxid aqueous solution of alkali metals to obtain the S-Omeprazole with high ee value, the S-Omeprazole and salt thereofobtained by the method have high ee value which is more than 99.2 percent, and the obtained S-Omeprazole has the color of kind of white, high yield and small pollution to the environment, and is suitable for industrial production.

Description

(1) Technical field [0001] The invention relates to a method for preparing S-omeprazole and its salt by inclusion and resolution of racemic omeprazole. (2) Background technology [0002] Omeprazole (trade name Losec) is developed by Astra Company in Sweden. It is the first proton pump inhibitor used clinically in the world. It is specially used to treat gastric ulcer, duodenal ulcer and reflux esophagitis ulcer. special medicine. [0003] S-omeprazole is the L-isomer of racemic omeprazole, compared to racemic and R-configured omeprazole, the curative effect of S-configured omeprazole Good, low toxicity and side effects. Optically active S-omeprazole magnesium salt (trade name Nexium) was first listed in Sweden in 2000. [0004] The chemical name of S-omeprazole is: (S)-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]- Sulfoxide}-1H-benzimidazole, the structural formula is as shown in formula I below: [0005] [0006] At present, there are three patent docume...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61P1/04
Inventor 沈正清焦华石建祥
Owner 安徽美诺华药物化学有限公司