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The preparation method of dex-ilaprazole potassium salt and the preparation method of dex-ilaprazole

A technology for ilaprazole potassium salt and potassium salt, which is applied in the field of medicine, can solve the problems of many impurities residues, poor e.e. value of dextro-ilaprazole, etc., and achieves high e.e. Effect

Active Publication Date: 2021-07-20
LIVZON PHARM GRP INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] But the e.e value of the dextro-ilaprazole obtained by the existing preparation method is not good, and there are many impurities remaining

Method used

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  • The preparation method of dex-ilaprazole potassium salt and the preparation method of dex-ilaprazole
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  • The preparation method of dex-ilaprazole potassium salt and the preparation method of dex-ilaprazole

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preparation example Construction

[0038] The application provides a preparation method of dex-ilaprazole potassium salt, which comprises the following steps:

[0039] Mix the crude product of D-ilaprazole (i.e. (+)-ilaprazole), alcohol solvent, first organic solvent and KOH to form potassium salt, and crystallize out the solid of D-ilaprazole potassium salt .

[0040] Specifically, in this application, (+)-ilaprazole is added to the mixed solvent of the alcohol solvent and the first organic solvent, then KOH is added and the potassium salt formation reaction is carried out at 15-30°C for 2-3h, and then The above reaction mixture was crystallized at 15° C.-30° C. for 2-3 hours, followed by solid-liquid separation to obtain dex-ilaprazole potassium salt as a solid. Among them, there are many ways of solid-liquid separation, including but not limited to: filtration, centrifugation and so on.

[0041] Among them, (+)-ilaprazole can be any e.e value, that is, the e.e value of (+)-ilaprazole crude product can be u...

Embodiment 1

[0065] Add (+)-ilaprazole 10g into a mixed solvent of 120mL dichloromethane and 30mL methanol, add 1.84g KOH (equivalent to (+)-ilaprazole molar ratio of 1.2), at 15-30°C Carry out the reaction of forming potassium salt, crystallize after about 2.5h, crystallize at 20°C-30°C for 2.5h, filter, and take the filter cake. Add appropriate amount of water and methanol to the filter cake, then add dilute acetic acid to adjust the pH value of the filtrate to 8-9; add 50mL of dichloromethane for extraction, take the organic phase, add anhydrous magnesium sulfate and triethylamine for drying, and filter out the desiccant , spin-dried; add 50mL isopropanol to the spin-dried product, stir at 15-30°C for 1.5h, then precipitate a solid, filter to obtain 5.3g of dex-ilaprazole. The e.e value of the filter cake is >98.0%, and the contents of the impurity ilaprazole sulfide and ilaprazole sulfone are both <0.2%; the e.e value of the final product is 99.0%, and the yield is 53%, and the impurit...

Embodiment 2

[0067] Add (+)-ilaprazole 20g into a mixed solvent of 240mL dichloromethane and 64mL methanol, add 3.67g KOH (equivalent to (+)-ilaprazole molar ratio of 1.2), at 15-30°C Carry out potassium salt reaction, crystallize after about 2.5h, crystallize at 15°C-30°C for 2.5h, filter, and take the filter cake. Add appropriate amount of water and methanol to the filter cake, then add dilute acetic acid to adjust the pH value of the filtrate to 8-9; add 100mL of dichloromethane for extraction, take the organic phase, add anhydrous magnesium sulfate and triethylamine for drying, and filter out the desiccant , spin-dried; add 110mL acetonitrile to the spin-dried product, stir at 15-30°C for 1.5h, then precipitate a solid, filter to obtain dex-ilaprazole 11g. The e.e value of the filter cake was >98.0%, and the contents of the impurity ilaprazole sulfide and ilaprazole sulfone were both <0.2%; the e.e value of the final product was 98.9%, and the yield was 55%, and the impurity ilaprazole...

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Abstract

The invention discloses a preparation method of dex-ilaprazole potassium salt and a preparation method of dex-ilaprazole, which relate to the technical field of medicine. The preparation method of the potassium salt of dex-ilaprazole comprises: mixing the crude product of dex-ilaprazole, an alcohol solvent, the first organic solvent and KOH to form a potassium salt, and then separating out the potassium salt of dex-ilaprazole solid. In this application, the crude product of D-ilaprazole is used as the starting material, mixed with alcohol solvent, the first organic solvent and KOH, stirred, and the potassium salt is generated through the potassium salt reaction, which can ensure the obtained D-ilaprazole The crystal form of the potassium salt of prazole remains consistent, and the solubility is basically the same, which is conducive to improving the subsequent preparation of dex-ilaprazole with high e.e value, high purity, impurity ilaprazole sulfone and ilaprazole sulfide content All below 0.2%. The preparation method is suitable for industrial production, and the difference between each batch is small.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of dex-ilaprazole potassium salt and a preparation method of dex-ilaprazole. Background technique [0002] Ilaprazole is a novel proton pump inhibitor for the treatment of duodenal ulcer, gastric ulcer and erosive esophagitis. Ilaprazole contains a chiral center and is a racemic mixture of two single enantiomers, the R and S enantiomers. Disclosed in CN101098867A is the preparation method of single enantiomer of ilaprazole, and animal experiments show that the optically pure isomers of ilaprazole, i.e., D- or L-ilaprazole and its racemate, are more effective in treating gastric acid It has a more excellent therapeutic effect in diseases related to too many diseases. [0003] At present, the method for obtaining optically pure ilaprazole isomers has an asymmetric chemical synthesis method, such as patent CN108689995A discloses 5-(1H-pyrrol-1-yl)-2-mercaptob...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14
CPCC07B2200/07C07D401/14
Inventor 谢诗琳王涛侯雪梅涂增清张象娜崔艳南李菁李普成张裕容吴小红莫雅婷陈乐平
Owner LIVZON PHARM GRP INC
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