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Industrial production method of azilsartan

A production method, the technology of candesartan, which is applied in the field of pharmaceutical production, can solve the problems that the cost and safety are not suitable for industrial production, cannot reach the medicinal level, and cannot be industrialized production, so as to achieve high economic value and social benefits, and increase the yield , The effect of reducing impurity B

Active Publication Date: 2014-02-26
合肥远志医药科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Chinese patent CN102344415A discloses that replacing hydroxylamine hydrochloride with 50% hydroxylamine solution can increase the yield, but the actual result still has a large amount of amide by-products, and the yield is about 51% to 55%. In addition, the 50% hydroxylamine solution is expensive and unsuitable. Shortcomings such as purchase, and there are safety factors (high temperature and explosive), it is not suitable for industrial production in terms of cost and safety
However, in actual results, we found that when there is water, the urea impurity (formula C) increases significantly after heating and recrystallization, and cannot meet the requirements of pharmaceutical grade. Therefore, the existing technical process has relatively large defects, and it is basically impossible to carry out industrial production.

Method used

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  • Industrial production method of azilsartan
  • Industrial production method of azilsartan
  • Industrial production method of azilsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The specific operation steps of producing Azilsartan are as follows:

[0030] 1. Formula III compound preparation:

[0031]

[0032] Add 4.0kg dimethyl sulfoxide, 2.0kg sodium bicarbonate, 1.4kg hydroxylamine hydrochloride, and raise the temperature to about 42±2°C. Stir the reaction for about 2 hours, cool down to 25±5°C, centrifuge, wash the filter cake with 1.4kg dimethyl sulfoxide, discard the filter cake, vacuum pump the filtrate directly into the reactor, heat up to 45±2°C and add 1.0kg candesartan C6 For alkyl esters (compounds represented by formula IV), heat up to 92±2°C and keep warm for 12 hours. HPLC confirms that the raw material is less than 1.0%. Cool down to 40°C and add 3.0kg of tap water dropwise, stop dripping until turbidity occurs, cool down in a circulating ice-salt bath (cooling in stages, takes 1hr) to 10°C, keep stirring for 2hrs, centrifuge to get wet products, return to the kettle for beating once ( 1.8Kg water), centrifuged and dried to ...

Embodiment 2

[0041] The specific operation steps of producing Azilsartan are as follows:

[0042] 1. Formula III compound preparation:

[0043]

[0044] Add 4.0kg of N-methylpyrrolidone, 1.0kg of anhydrous sodium carbonate, and 1.3kg of hydroxylamine hydrochloride, and raise the temperature to about 30-40°C. Stir the reaction for about 2 hours, cool down to 30±5°C, centrifuge, add 1.0kg N-methylpyrrolidone to wash the filter cake, discard the filter cake, vacuum pump the filtrate directly into the reactor, heat up to 45±2°C and add 1.0kg candesartan C6 alkyl esters (compounds represented by formula IV), heated up to 95±5°C and incubated for 20 hours, HPLC confirmed that the raw materials were less than 1%. Cool down to 40°C and add 3.5kg of tap water dropwise, stop dripping until turbidity occurs, cool down in a circulating ice-salt bath (cooling in stages, takes 1hr) to 10°C, keep stirring for 2hrs, centrifuge to obtain wet products, return to the kettle for beating once ( 2.0kg of w...

Embodiment 3

[0053] The specific operation steps of producing Azilsartan are as follows:

[0054] 1. Formula III compound preparation:

[0055]

[0056] Add 4.0kg of N,N-dimethylacetamide, 1.35kg of potassium bicarbonate, and 1.4kg of hydroxylamine hydrochloride, and raise the temperature to about 30-40°C. Stir the reaction for about 2 hours, cool down to 25±5°C, centrifuge, add 1.0kg N,N-dimethylacetamide to wash the filter cake, discard the filter cake, vacuum pump the filtrate directly into the reactor, heat up to 55±2°C and add 1.0kg Candesartan C6 alkyl ester (compound represented by formula IV), heat up to 102±3°C and keep warm for 24hrs, and HPLC confirms that the raw material is less than 1%. Cool down to 40°C and add 3.2kg of tap water dropwise, stop dripping until turbidity occurs, cool down in a circulating ice-salt bath (cooling in stages, takes 1hr) to 10°C, keep stirring for 2hrs, centrifuge to get wet products, return to the kettle for beating once ( 2.0kg of water), ce...

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Abstract

The invention provides an industrial production method of azilsartan. The method comprises the following steps: 1) replacing hydroxylamine hydrochloride and organic alkali or inorganic alkali in a polarity aprotic solvent and centrifuging to obtain a homogeneous system, adding candesartan C6 alkyl ester (a compound shown in formula IV) and reacting at 90-110 DEG C to obtain a compound shown in formula III; and 2) dissolving the compound shown in formula III and a carbonylation reagent in the polarity aprotic solvent, adding in the organic alkali or inorganic alkali and reacting at 0-40 DEG C to obtain a compound shown in formula II, and carrying out alkaline hydrolysis to obtain azilsartan. By adopting the preparation method, the production cost of azilsartan is greatly reduced, an expensive and unstable hydroxylamine solution is not used, the reaction temperature is lowered, the product quality is well improved, the requirement for medicinal level is met, and individual impurity is controlled below 0.1%, which is superior to the ICH requirement of the EU (European Union).

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to an industrial production method of azilsartan. Background technique [0002] Azilsartan is a new angiotensin II receptor antagonist that lowers blood pressure by blocking the effects of angiotensin II and vasopressor hormones. The drug was launched by Takeda Pharmaceutical Company of Japan in 2012 for the treatment of hypertension. treat. [0003] Chinese patent CN102344415A discloses that replacing hydroxylamine hydrochloride with 50% hydroxylamine solution can increase the yield, but the actual result still has a large amount of amide by-products, and the yield is about 51% to 55%. In addition, the 50% hydroxylamine solution is expensive and unsuitable. There are disadvantages such as purchasing, and there are safety factors (high temperature and explosion), and it is not suitable for industrial production in terms of cost and safety. Chinese pat...

Claims

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Application Information

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IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 胡孟奇刘斐孙松
Owner 合肥远志医药科技开发有限公司
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