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Synthetic method of high-purity azilsartan medoxomil impurity

A technology of azilsartan medoxomil and a synthetic method, applied in the synthesis field of high-purity azilsartan medoxomil impurity, can solve the problems such as no impurity I purification method reported in the literature, no specific report impurity purification method, etc., and achieves high purity, Simple synthesis and high yield

Inactive Publication Date: 2018-11-09
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] , but there is no specific report on the purification method of this impurity. At present, there is no literature report on the purification method of impurity I

Method used

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  • Synthetic method of high-purity azilsartan medoxomil impurity
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  • Synthetic method of high-purity azilsartan medoxomil impurity

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Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1: add 10g Azilsartan, 6.5g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, 3.7g potassium carbonate, 0.5g iodine in reaction flask Sodium chloride and 45g dimethyl sulfoxide were heated to 35°C for 3h.

[0024] After the reaction is completed, filter, add 50g of dichloromethane and 50g of purified water to the filtrate, after separation, extract the water layer once with 20g of dichloromethane, combine the dichloromethane layers, wash with brine once, concentrate under reduced pressure, add 50g of methanol was stirred at 30°C for 5h, and the crude impurity was obtained by filtration.

[0025] Add 30 g of methanol to the crude product, stir to raise the temperature, filter, cool down to crystallize, filter, and dry to obtain 10.5 g of refined azilsartan medoxomil impurity, with a total yield of 70.5% and a liquid phase purity of 99.1%.

Embodiment 2

[0026] Example 2: 10g Azilsartan, 6.5g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, 3.5g sodium carbonate, 0.5g iodine were added to the reaction flask Sodium chloride and 45g N,N-dimethylacetamide were heated to 35°C for 3h.

[0027] After the reaction is completed, filter, add 50g of dichloromethane and 50g of purified water to the filtrate, after separation, extract the water layer once with 20g of dichloromethane, combine the dichloromethane layers, wash with brine once, concentrate under reduced pressure, add 50g of methanol was stirred at 30°C for 5h, and the crude impurity was obtained by filtration.

[0028] Add 30 g of methanol to the crude product, stir to raise the temperature, filter, cool down to crystallize, filter, and dry to obtain 12.3 g of fine azilsartan medoxomil impurity, with a total yield of 82.6% and a liquid phase purity of 99.9%.

[0029] The product is identified by mass spectrometry: figure 1 It is the mass spectrum of azilsartan medoxomil impurity I...

Embodiment 3

[0039] Example 3: 10g Azilsartan, 9.7g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, 6.5g sodium carbonate, 3.0g iodine were added to the reaction flask Sodium chloride and 45g N,N-dimethylacetamide were heated to 35°C for 3h.

[0040] After the reaction is completed, filter, add 50g of dichloromethane and 50g of purified water to the filtrate, after separation, extract the water layer once with 20g of dichloromethane, combine the dichloromethane layers, wash with brine once, concentrate under reduced pressure, add 50g of methanol was stirred at 30°C for 5h, and the crude impurity was obtained by filtration.

[0041] Add 30 g of methanol to the crude product, stir to raise the temperature, filter, cool down to crystallize, filter, and dry to obtain 12.1 g of fine azilsartan medoxomil impurity, with a total yield of 81.2% and a liquid phase purity of 99.9%.

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Abstract

The invention discloses a synthetic method of a high-purity azilsartan medoxomil impurity. The method comprises the steps of with azilsartan as a raw material, reacting with 4-chloromethyl-5-methyl-1,3-dioxol-2-ketone in an alkaline organic solvent so as to prepare an azilsartan medoxomil impurity, refining the azilsartan medoxomil impurity through an organic solvent, so as to obtain the refined high-purity azilsartan medoxomil impurity. According to the synthetic method, the blank in the method for preparing the impurity at present is filled up, the synthetic method has the advantages of simplicity in operation and high yield and purity, can be applied to the research of the azilsartan medoxomil impurity and is capable of helping people to design a reaction route, improve reaction conditions, reduce or avoid the generation of the impurities and well improve the product quality in the synthetic process of azilsartan medoxomil.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing high-purity azilsartan medoxomil impurities. Background technique [0002] Azilsartan (Azilsartan) is an angiotensin II receptor antagonist drug developed by Japan's Takeda Pharmaceutical Company (Takeda) for the treatment of hypertension. Drugs are used together. Because the drug has good clinical trial results, it is regarded as the next-generation product of candesartan cilexetil. In addition, it can overcome the shortcomings of tetrazole in terms of synthesis and metabolism, has higher oral bioavailability, and has a more significant effect on lowering blood pressure. The drug completed Phase III clinical trials on April 28, 2010, and received FDA marketing approval in 2012. [0003] The study of impurities is helpful to the optimization of the synthesis process and quality control of the drug. The study of the impurities of azilsarta...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 孙翔覃志俊黄永洲王竞存蔡强周爱新兰柳琴祁红林黄肖艳
Owner 珠海润都制药股份有限公司
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