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Method for preparing and purifying (L)-pantoprazole sodium

A technology of levo-pantoprazole sodium and pantoprazole, which is applied in the field of preparation and purification of levo-pantoprazole sodium, can solve problems such as inapplicability to large-scale production, cumbersome post-processing, and influence on the purity of salt formation, and achieve reaction Mild conditions, high yield and simple operation

Inactive Publication Date: 2012-03-21
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The method for prior art preparation levopantoprazole sodium counterpart is described in WO9208716 and WO9627989, and WO9208716 is synthesized by the method for splitting, and this method makes the required cost of pantoprazole sodium optical enantiomer larger, and does not need It is suitable for large-scale production; WO9627989 is synthesized by chiral oxidation, which is easy to carry out, but the post-treatment is cumbersome and many by-products are generated in the reaction, which has a great impact on the purity of the salt.

Method used

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  • Method for preparing and purifying (L)-pantoprazole sodium

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Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of L-pantoprazole

[0029] Add 1kg of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzimidazole, 7.5L of toluene, D-diethyl tartrate (DET) 374g, tetraisopropyl titanate 256g and appropriate amount of water (the water content in the reaction system is about 7ml), stir and heat up to 60-65°C to form a transparent solution, keep stirring for 1 hour, the reaction solution Cool down to 5-10°C, add 153ml of N,N-diisopropylethylamine, then slowly add 1kg of dicumyl hydroperoxide (DCP, concentration 80%) dropwise three times, react at -2-0°C for 20 Hours, use HPLC to trace the residue of raw materials to less than 1% as the end point of the reaction. After the reaction, filter the reaction solution, wash the filter cake with methyl tert-butyl ether, and dissolve the washed white powder solid in 3L 2% NaOH Add 2% medicinal charcoal to the solution, stir for 20 minutes to decolorize, and filter to remove medicinal charcoal. The...

Embodiment 2

[0031] Embodiment 2: the preparation of L-pantoprazole

[0032] Add 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzimidazole 1kg, ethyl acetate 7.5 L, D-diethyl tartrate (DET) 374g, tetraisopropyl titanate 256g and water 10ml, stir and heat up to 60-65°C to form a transparent solution, keep stirring for 1 hour, and cool the reaction solution to 5-10°C, Add 153ml of N,N-diisopropylethylamine, then slowly add 1kg of dicumyl hydroperoxide (DCP, concentration 80%) dropwise three times, react at -5-0°C for 24 hours, and follow up to the raw material by HPLC The residue is reduced to less than 1% as the end point of the reaction. After the reaction is over, filter the reaction solution, wash the filter cake with methyl tert-butyl ether, dissolve the washed white powder solid in 3L 2% NaOH solution, add 2% Medicinal charcoal was stirred for 20min for decolorization, and the medicinal charcoal was removed by filtration. The filtrate was adjusted to pH 9-10 with...

Embodiment 3

[0034] Embodiment 3: the preparation of L-pantoprazole sodium

[0035] Suspend 0.56 kg of dry L-pantoprazole in 1.4 L of isopropanol, add dropwise sodium hydroxide solution (67.8 g of sodium hydroxide dissolved in 67.8 ml of water) at 25-30° C., and stir until the solution becomes clear. Add 6L of methyl tert-butyl ether, lower the temperature to -5~0°C and stir for 2 hours to precipitate a solid, filter, wash the filter cake with 3L of methyl tert-butyl ether, and dry at 40~45°C for 12 hours under reduced pressure (93kPa) , 0.51kg of white crystalline powder was obtained, the yield was 89.2%, melting point: 146.8~147.5°C, [a] D 20 =-121.7 (acetonitrile:methanol=1:1).

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Abstract

The invention provides a method for preparing (L)-pantoprazole sodium, which comprises the following steps of: oxidizing 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]thio}-1H-benzimidazole by using 3,5-diisopropylbenzene hydroperoxide under the catalysis of a tetraisopropyl titanate, D-(-)-diethyl tartrate and N,N-diisopropylethylamine system to obtain S-(-)-5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole, namely (L)-pantoprazole, refining the (L)-pantoprazole, and preparing a salt to obtain the (L)-pantoprazole sodium.

Description

Technical field: [0001] The invention relates to a preparation and purification method of L-pantoprazole sodium. technical background: [0002] Levpantoprazole Sodium (Levpantoprazole Sodium), chemical name S-(-)-5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl] Sulfonyl]-1H-benzimidazole sodium is the third-generation proton pump inhibitor after omeprazole and lansoprazole, and it is currently used in clinical pantoprazole. Sodium salt of single enantiomer S-(-)-pantoprazole. The feature of this drug is that it is not easy to interact with cytochrome p450 in the metabolic process to cause oxidation failure, and its bioavailability is 7 times higher than that of omeprazole. Lansoprazole is also more stable than omeprazole and lansoprazole in a weakly acidic environment. The drug is mainly used to treat diseases related to gastric acid secretion disorders, such as gastric ulcer, duodenal ulcer, reflux esophagitis and Zoller-Ellison syndrome. It has been clinically pr...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 强建华魏红亮
Owner HC SYNTHETIC PHARMA CO LTD
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