Preparation and purification method of pantoprazole optical antimer

A technology of pantoprazole and a purification method, which is applied in the direction of organic chemistry, etc., can solve the problems of high cost of pantoprazole sodium optical antipodes, insufficient optical purity, and influence on the purity of salt formation, so as to improve synthesis efficiency, The effect of shortening the reaction time and increasing the production yield

Inactive Publication Date: 2014-05-21
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Prior art has two kinds of methods for preparing pantoprazole optical antipodes described in WO9208716 and W09627989, and WO9208716 is synthesized by the method of resolution, and the required cost of pantoprazole sodium optical antipodes is made by this method is relatively large , not suitable for large-scale production; W09627989 is synthesized by chiral oxidation, which is easy to carry out, but the post-processing is cumbersome and the reaction produces many by-products, which have a great impact on the purity of the salt
Chinese patent CN102382103A is also synthesized by chiral oxidation. The reaction process is simple and the reaction conditions are mild. The disadvantage is that the reaction time is long and the optical purity is not high enough.

Method used

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  • Preparation and purification method of pantoprazole optical antimer
  • Preparation and purification method of pantoprazole optical antimer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of L-pantoprazole

[0036] In a 10L reactor, put in 4.8L of toluene, and put in 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzene under stirring and imidazole 1kg, heated to 70°C in a jacketed water bath and stirred to dissolve. Cool in a water bath to 50°C, add 374 g of D-diethyl tartrate (DET) dropwise, and keep stirring for 20 minutes. Add 7ml of water and 256g of tetraisopropyl titanate, immediately stop stirring and let it stand for 40 minutes, cool down to 25-26°C in a jacketed water bath, add 153ml of N,N-diisopropylethylamine dropwise, and then add peroxide Hydrogen cumene (CHP, concentration 80%) 660g, temperature control 28~30℃, about 1 hour. The addition was complete and stirred for an additional 2 hours. Filter and wash the filter cake with 3L of methyl tert-butyl ether. Filter, drain, and dry at room temperature to obtain 656 g of off-white solid powder, which is the crude product of L-pantoprazole. ...

Embodiment 2

[0038] Embodiment 2: the preparation of L-pantoprazole

[0039]In a 10L reactor, put 7.5L of toluene into it, and put 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzene under stirring and imidazole 1kg, heated to 70°C in a jacketed water bath and stirred to dissolve. Cool in a water bath to 50°C, add 374 g of D-diethyl tartrate (DET) dropwise, and keep stirring for 20 minutes. Add 7ml of water, 256g of tetraisopropyl titanate, stop stirring immediately and let it stand for 40 minutes, cool down to 25-26°C in a jacketed water bath, add 153ml of N,N-diisopropylethylamine dropwise, and then add peroxide Hydrogen cumene (CHP, concentration 85%) 621g, temperature control 28~30℃, about 1 hour. The addition was complete and stirred for an additional 2 hours. After filtering, the filter cake was beaten and washed with 4L of methyl tert-butyl ether. Filter, drain, and dry at room temperature to obtain 685 g of off-white solid powder, which is the crude product...

Embodiment 3

[0041] Embodiment 3: the preparation of dexpantoprazole

[0042] In a 10L reactor, put in 5.5L of toluene, and put in 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfur]-1H-benzene under stirring and imidazole 1kg, heated to 70°C in a jacketed water bath and stirred to dissolve. Then it was cooled to 50° C. in a water bath, 374 g of L-diethyl tartrate was added dropwise, and the mixture was stirred and kept for 20 minutes. Add 7ml of water, 256g of tetraisopropyl titanate, stop stirring immediately and let it stand for 40 minutes, cool down to 25-26°C in a jacketed water bath, add 153ml of N,N-diisopropylethylamine dropwise, and then add peroxide Hydrogen cumene (CHP, concentration 80%) 660g, temperature control 28~30℃, about 1 hour. The addition was complete and stirred for an additional 2 hours. After filtering, the filter cake was beaten and washed with 3.5 L of methyl tert-butyl ether. Filter, drain, and dry at room temperature to obtain 664 g of off-white so...

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Abstract

The invention provides a preparation and purification method of a pantoprazole optical antimer. The method comprises the following steps: carrying out a reaction on 5-difloromethoxyl-2-{[(3, 4-dimethoxyl-2-pyridyl)methyl]sulfur}-1H-benzimidazole and optically active diethyl tartrate (D-(-)-diethyl tartrate or L-(+)-diethyl tartrate) according to different feeding sequences; reacting completely within 2 hours and filtering to obtain optically active pantoprazole; then, purifying to obtain a pure product S-(-)-pantoprazole or R-(+)-pantoprazole. The method provided by the invention is simple and convenient to operate, higher in product purity and high in yield, and the reaction time is shortened and the production cost is saved, so that the method is more suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a preparation and purification method of pantoprazole optical antipodes. Background technique [0002] Pantoprazole (Pantoprazole), chemical name 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole , is a new type of proton pump inhibitor, which is mainly used clinically for anti-digestive ulcer, spasm, and treatment of gastro-duodenal ulcer, esophagitis, and gastro-esophageal reflux disease. After taking it, it can accumulate in the parietal cells of the gastric mucosa and convert into an active metabolite - sulfenamide. The active substance can inhibit the H+ / K+-ATPase that stimulates gastric parietal cells to secrete gastric acid, thereby exerting an acid-suppressing effect. It has the characteristics of safety, reliability, and small toxic and side effects. [0003] Prior art has two kinds of methods for preparing pantoprazole optical antipodes described in WO9208716 and W09627989, and WO9208...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 杨成强建华魏红亮
Owner HC SYNTHETIC PHARMA CO LTD
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