A kind of preparation method of pantoprazole sodium sulfone nitrogen oxide impurity

A technology for pantoprazole sodium and oxidized impurities, applied in the field of medicine, can solve problems such as being difficult to remove, and achieve the effects of cheap raw materials, high yield and simple preparation method

Active Publication Date: 2017-08-08
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And if the sulfone nitrogen oxide impurities are produced, it is difficult to remove them in the subsequent refining process

Method used

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  • A kind of preparation method of pantoprazole sodium sulfone nitrogen oxide impurity
  • A kind of preparation method of pantoprazole sodium sulfone nitrogen oxide impurity
  • A kind of preparation method of pantoprazole sodium sulfone nitrogen oxide impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Add 10g 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (compound 1), 10g 5-difluoromethoxy-2-mercapto-1H-benzimidazole to the reaction flask (Compound 2), 100ml of dichloromethane, stirred, dropwise added 130g of 10% sodium hydroxide solution, stirred at 20-30°C for 2h, allowed to stand for layers, washed the dichloromethane layer twice with 30ml of water each time, Then underpressure distillation obtains yellow oil 16.6g (intermediate 3);

[0031] (2) Dissolve the yellow oil in step (1) with 40ml acetic acid, add 15.8g 50% hydrogen peroxide, 0.68g methyl rhenium trioxide (MTO), heat up to 95°C, and react for 6h; after the reaction is completed, pour the reaction solution Pour it into 100ml of water, adjust the pH to neutral with 10% sodium hydroxide solution, extract the aqueous layer with 50ml (each amount) of dichloromethane three times, and distill the dichloromethane under reduced pressure to obtain a yellow oily substance. Dissolve the oil in 20ml of tolu...

Embodiment 2

[0034] (1) Dissolve the yellow oil in step (1) of Example 1 with 45ml of acetic acid, add 18.2g of 50% hydrogen peroxide, 0.88g of methyl rhenium trioxide (MTO), heat up to 95°C, and react for 7h; after the reaction is completed, The reaction solution was poured into 100ml of water, and the pH was adjusted to be neutral with 10% sodium hydroxide solution. The aqueous layer was extracted three times with 50ml (each dosage) of dichloromethane, and the dichloromethane was distilled under reduced pressure to obtain a yellow oil. Dissolve the oil in 23ml of toluene, add 175ml of methyl tert-butyl ether, stir for 1h, and filter with suction to obtain 14.1g of a light yellow solid (Intermediate 4), with a purity of 97.5% and a molar yield of 76.0%;

[0035] (2) Dissolve 14.1g of intermediate 4 in 23ml of acetone, add 8.5g of 20% sodium hydroxide solution, cool down to 0°C and stir for 30min, and suction filter to obtain 13.2g of white solid with a purity of 98.4% and a molar yield of ...

Embodiment 3

[0036] (1) The yellow oil of step (1) of Example 1 was dissolved with 50ml of acetic acid, 22.0g of 50% hydrogen peroxide was added, 1.0g of methyl rhenium trioxide (MTO), the temperature was raised to 95°C, and the reaction was carried out for 8h; after the reaction was completed, The reaction solution was poured into 100ml of water, and the pH was adjusted to be neutral with 10% sodium hydroxide solution. The aqueous layer was extracted three times with 50ml (each dosage) of dichloromethane, and the dichloromethane was distilled under reduced pressure to obtain a yellow oil. Dissolve the oil in 25ml of toluene, add 180ml of methyl tert-butyl ether, stir for 1h, and filter with suction to obtain 14.6g of a light yellow solid (Intermediate 4), with a purity of 97.8% and a molar yield of 78.6%;

[0037] (2) Dissolve 14.6g of intermediate 4 in 25ml of acetone, add 8.8g of 20% sodium hydroxide solution, cool down to 0°C and stir for 30min, and filter with suction to obtain 13.8g o...

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Abstract

The invention discloses a method for preparing a pantoprazole sodium sulfone-nitrogen oxidized impurity. The method comprises the steps: enabling 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride, which serves as a raw material, to react with 5-difluoromethoxy-2-mercapto-1H-benzimidazole so as to produce 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfo}-1H-benzimidazole; then, oxidizing 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfo}-1H-benzimidazole in the presence of hydrogen peroxide and acetic acid in a manner of using methyl rhenium trioxide as a catalyst, so as to produce a sulfone-nitrogen oxidized product of pantoprazole; and finally, forming a sodium salt by the sulfone-nitrogen oxidized product of pantoprazole and sodium hydroxide, thereby obtaining the pantoprazole sodium sulfone-nitrogen oxidized impurity. According to the method, the hydrogen peroxide-acetic acid system can oxidize a pyridine ring. The oxidizer methyl rhenium trioxide is adopted as the catalyst and can be complexed with hydrogen peroxide so as to produce peroxide of rhenium, oxygen in the peroxide of rhenium can be transferred to thioether needing oxidization, and thioether can be oxidized into sulfone through controlling the usage amount of the catalyst and the reaction temperature, so that the high-yield and high-purity product can be obtained.

Description

technical field [0001] The invention belongs to the technical field of medicines, and more specifically relates to a method for preparing sulfone nitrogen oxide impurities produced in the preparation process of pantoprazole sodium. Background technique [0002] Pantoprazole sodium is a national fourth-class new drug and a first-line treatment drug for peptic ulcer disease. So far, it has been approved for use in 20 countries including the United Kingdom, Germany, and Mexico. Pantoprazole sodium was developed by Byk Gulden of Germany, and its preparation was developed by Wyeth of the United States. It was launched in Sweden in 1994 and is the third generation proton pump inhibitor after omeprazole sodium and lansoprazole. In order to ensure the drug safety and quality of pantoprazole sodium, it is necessary to carry out rigorous research on related impurities and control the impurities within safe and reasonable limits. The structural formula of pantoprazole sodium is shown ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 秦春霞吴柯李保勇张兆珍董廷华
Owner 山东安信制药有限公司
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