Preparation method of chiral pantoprazole and sodium salt thereof

A technology of pantoprazole sodium and pantoprazole, which is applied in the field of preparation of chiral pantoprazole and its sodium salt, can solve the problem of insufficient optical purity and chemical purity of the product, complex post-treatment process, enantioselective The problem of low reactivity is solved, and the effects of simple post-treatment method, less solvent consumption and high enantioselectivity are achieved.

Inactive Publication Date: 2015-11-04
CHANGZHOU INST OF CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The above method has the defects of low enantioselectivity, low yield, expensive catalyst or too low reaction temperature; in addition, pantothioether is easily over-oxidized to produce by-product sulfone, and the properties of sulfone are similar to the product sulfoxide and are difficult to remove. The above method either does not disclose a reasonable post-treatment method after the oxidation reaction is completed, or the post-treatment process is extremely complicated, and the optical purity and chemical purity of the final product are not high enough

Method used

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  • Preparation method of chiral pantoprazole and sodium salt thereof
  • Preparation method of chiral pantoprazole and sodium salt thereof
  • Preparation method of chiral pantoprazole and sodium salt thereof

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Effect test

Embodiment 1

[0049] 3.674g 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfanyl]-1H-benzimidazole (10mmol), 1.225g Mix N,N'-diethyl-(S,S)-tartrate diamide (6mmol) and 20mL toluene and heat up to 80°C (internal temperature); add 0.9mL tetraisopropoxytitanium (3mmol), keep at 80°C Stir for 1h; then add 54 μL of water (3mmol), and stir for 1h at 80°C; after cooling to 30°C, add 3.6mL of cumene hydroperoxide (20mmol), and react for 2h to terminate the reaction, and measure S-pantoprazole by HPLC The enantiomeric excess value is 91.87%, the conversion rate is 48.44%, and the content of peroxidation by-product sulfone is 0%.

Embodiment 2

[0051] 3.674g 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfanyl]-1H-benzimidazole (10mmol), 1.394g N,N'-di-n-propyl-(S,S)-tartaric acid diamide (6mmol) and 20mL toluene were mixed and heated to 80°C (internal temperature); 0.9mL tetraisopropoxytitanium (3mmol) was added, 80°C Keep stirring for 1 hour; then add 54 μL of water (3 mmol) and stir at 80°C for 1 hour; after cooling down to 30°C, add 3.6 mL of cumene hydroperoxide (20 mmol) and react for 2 hours to terminate the reaction. The enantiomeric excess of azole is 95.26%, the conversion rate is 36.65%, and the content of peroxidation by-product sulfone is 0.21%.

Embodiment 3

[0053] 3.674g 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfanyl]-1H-benzimidazole (10mmol), 1.562g Mix N,N'-di-n-butyl-(S,S)-tartrate diamide (6mmol) and 20mL toluene and heat up to 80°C (internal temperature); add 0.9mL tetraisopropoxytitanium (3mmol), 80°C Keep stirring for 1 hour; then add 54 μL of water (3 mmol) and stir at 80°C for 1 hour; after cooling down to 30°C, add 3.6 mL of cumene hydroperoxide (20 mmol) and react for 2 hours to terminate the reaction. The enantiomeric excess of azole was 89.48%, the conversion rate was 28.12%, and the content of peroxidation by-product sulfone was 0%.

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Abstract

The invention provides a preparation method of chiral 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfinyl]-1H-benzimidazole (pantoprazole) and a sodium salt thereof. The method comprises the following steps: in an organic solvent, adding an organic alkali in the presence of a chiral titanium complex prepared from a diamide R,R or S,S-tartrate ligand, a metal titanium reagent and water, and oxidizing prochiral thioether of pantoprazole by a hydrogen peroxide oxidizer to obtain the corresponding pantoprazole containing rich single antipode. The method has the advantages of high enantioselectivity, mild reaction, simple after-treatment process, fewer procedure steps, low solvent consumption and low cost, and is very simple to operate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of chiral pantoprazole with anti-peptic ulcer activity and its sodium salt. Background technique [0002] Pantoprazole, chemical name 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl-1H-benzimidazole, is an inhibitor of A proton pump inhibitor of gastric acid secretion, used to treat diseases related to gastric acid secretion disorders such as peptic ulcer and reflux esophagitis. The compound has a sulfur-containing chiral center. Studies have proved that the S-configuration of pantoprazole has better curative effect, higher bioavailability, and lower side effects than its racemate and R-configuration, so the optical The research on the preparation method of pure pantoprazole is of great significance. [0003] DE4035455 disclosed for the first time a method for separating (pyridyl-methyl)sulfinyl-1H-benzimidazole into single enant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 王启卫曾银凤朱槿邓金根王红丹彭丽君
Owner CHANGZHOU INST OF CHEM
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