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Pantoprazole sodium and preparation method thereof

A technology of pantoprazole sodium and benzimidazole, which is applied in the field of medicine and can solve the problems of excessive impurity C content, many side reactions, and cumbersome steps

Active Publication Date: 2019-02-19
CHENGDU TIANTAISHAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] CN101475561A discloses the preparation method of pantoprazole sodium monohydrate, and this method step is loaded down with trivial details, and side reaction is more
However, the present inventors have found that the impurity C content in the product obtained by the CN103232438A method is as high as 0.09%, although it is qualified, it is still close to the upper limit of the limit, which is completely undesirable, because the prepared raw material There will also be some events, such as storage, transportation, and preparation of preparations, which may lead to excessive levels of impurity C in the product

Method used

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  • Pantoprazole sodium and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Embodiment 1: Preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III)

[0169]

[0170] Add 9.22kg of toluene, add 1.5kg of 2-hydroxymethyl-3,4-dimethoxypyridine at room temperature, cool down to 3°C-10°C, add 1.63kg of chloride within 1-2 hours at 3-10°C After the addition of sulfoxide, keep stirring at 5-10°C for 1 hour, heat up to 35-40°C within 1 hour, and keep warm at 35-40°C for 4 hours. TLC detection After the reaction is completed, the temperature is controlled at 35-40°C, vacuum distilled thionyl chloride for 3-4 hours, and 9kg of toluene is added, the temperature is lowered to 20-25°C, centrifugal suction filtration, 0.64L toluene washes the filter cake, drains, 50 Blast drying at -55°C for 6-8 hours to obtain 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III).

Embodiment 2

[0171] Example 2: Preparation of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzo Imidazole (IV)

[0172]

[0173] Add 1.0kg of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) to 6.0kg of purified water at 25°C, stir at 25°C to 30°C for 30 minutes, and filter with suction, 2.0kg Wash the filter paper with purified water to obtain filtrate A (stand-by);

[0174] Dissolve 0.7857kg of sodium hydroxide in 1.4293kg of purified water at room temperature, raise the temperature to 40°C, and add 1.0715kg of 5-difluoromethoxy-2-mercapto-1H-benzimidazole in batches within 30 minutes. Add the filtrate A dropwise at 40-45°C within 2-2.5 hours, keep the reaction at 48-52°C for 6 hours, TLC detects that it is below the limit; slowly cool down to 15°C, keep warm and crystallize at 13-17°C for 3-6 hours, Suction filtration, rinse the solid with 1.46kg of purified water, drain, and air-dry at 40-45°C for 10 hours to obtain crude product IV;

[0175] Add 1 kg ...

Embodiment 21

[0176] Example 21: Preparation of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzo Imidazole (IV)

[0177] This embodiment provides another method for preparing 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzimidazole (IV) method.

[0178] Add 2500ml of water and 204g of NaOH into the glass reactor and stir to dissolve, then add a mixture of 4000g of methanol and mercapto (5-difluoromethoxy-2mercapto-1H-benzimidazole, 500g). After heating to 40°C, add pyridine hydrochloride (2-chloromethyl-3,4-dimethoxypyridine hydrochloride, 500g), heat up to 50-55°C and react for 3.5 hours. After the reaction, release the reaction Liquid, use a rotary evaporator to steam methanol under reduced pressure, control the internal temperature to not exceed 50°C, evaporate as much as possible, then transfer the material to a stirred reaction tank, add 3000ml of dichloromethane, fully stir and dissolve, let stand to separate layers, and separate The aqueous l...

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Abstract

The invention relates to pantoprazole sodium and a preparation method thereof, in particular to a method of preparing pantoprazole sodium. The method comprises the steps of 1) using 2-hydroxymethyl-3,4-dimethoxypyridine (II) as a start material to generate a compound of formula III under the action of a chloride; 2) subjecting the compound of formula III and 5-difluoromethoxy-2-thiol-1H-benzimidazole to condensation in the presence of an inorganic base so as to generate a compound of formula IV; 3) using an oxidant to oxidize the compound of formula IV to generate 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole, namely, pantoprazole; 4) allowing the obtained 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole to react with sodium hydroxide to generate a salt, namely, pantoprazole sodium (I); and optionally 5) refining the pantoprazole sodium. The product prepared via the method has high purity; related impurities, such as oxidation impurity, reduction impurity, decomposition impurity, have low contents.

Description

technical field [0001] The invention belongs to the technical field of medicines and relates to pantoprazole sodium which can be used for treating stomach diseases. Pantoprazole sodium of the present invention has good properties. The invention also relates to a preparation method of pantoprazole sodium. Background technique [0002] Digestive system disease is a common and frequently-occurring disease, and it is also a chronic disease that is very easy to relapse. So far, there is no effective way to completely cure it. This has become one of the key topics in the field of pharmaceutical research. Statistical analysis shows that the incidence rate of digestive system diseases in the world accounts for 10-12% of human beings, and the incidence rate of digestive system diseases in cities and towns in my country is 11.43%, which is basically similar to many developed countries in Europe and America. Due to the characteristics of diet structure, the prevalence rate of residen...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 王敬江威谢晓飞曾业浩王薇龚诗雨赵东明
Owner CHENGDU TIANTAISHAN PHARMA
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