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Impurity content decreasing method

A technology of impurity and content, applied in the direction of organic chemistry, can solve problems such as difficult to remove, product loss, API difficult to meet ICHQ7, etc., and achieve the effect of facilitating recycling and easy operation

Active Publication Date: 2015-07-29
安徽省凤阳县御膳油脂有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This azilsartan tetramer impurity (4) has a high content and is difficult to remove later, making it difficult for the API to meet the standards stipulated in ICH Q7
In the process of drug synthesis, the impurities are generally reduced and the purity of the product is improved through repeated recrystallization, but repeated recrystallization can easily lead to product loss and yield decline

Method used

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Experimental program
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Embodiment 1

[0031] The preparation of embodiment 1 Azilsartan

[0032] At room temperature (30°C), compound 01 (180g, 1eq), toluene (540mL) and triethylamine (47.6g, 1.2eq) were added to the reaction flask to obtain a mixture, ethyl chloroformate (51.1g, 1.2eq) Toluene (180mL) solution was added dropwise to the above reaction solution. After the drop was completed, the stirring was continued for 2h. After the reaction, the reaction solution was cooled to room temperature, 600mL of water was added, the toluene layer was separated, and DMAP (57.5g , 1.2eq), heated to reflux, stirred for 3h, after the reaction, the reaction solution was cooled to room temperature, 1.2L of 2mol / L sodium hydroxide aqueous solution was added dropwise and stirred for 3h, the pH value of the reaction solution was adjusted to 3.0, and kept stirring for 1h , filtered with suction, the solid was rinsed with 200 mL of water, and the solid was vacuum-dried at 50° C. for 12 hours to obtain azilsartan (2) in a total yie...

Embodiment 2

[0033] The impact of the amount of embodiment 2 alkali on azilsartan tetramer impurity content

[0034] Azilsartan (8.59 g, 18.84 mmol), DMAc (80 ml), DMAP (0.5 g), TsCl (3.9 g), 4-hydroxymethyl-5-methyl After -1,3-dioxol-2-one (2.4g) was stirred and dissolved, the base in Table 1 was added, and the dropwise addition was completed. The mixture was heated to 10° C., kept stirring for 3 hours, and the reaction was completed. Add 0.3N HCl dropwise to the reaction solution, adjust the pH to 5, then slowly add 60ml of water dropwise, precipitate a solid, filter, add dropwise 80ml of acetone / water (V / V is 1:3) to the obtained solid, After stirring at 35°C for 2 hours, stirring in an ice bath for 3 hours, filtering, and vacuum drying at 50°C for 10 hours, 7.8 g of azilsartan medoxomil was obtained. The HPLC purity of azilsartan medoxomil and azilsartan tetramer The impurity content is as shown in Table 1:

[0035] Table 1, the impact of the amount of alkali on the impurity content ...

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Abstract

The invention relates to an impurity content decreasing method, in particular to a preparation method of azilsartan medoxomil with low content of azilsartan tetramer impurities (4). The method comprises the step that azilsartan (2) reacts with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (3) in the presence of an alkali. The method is characterized in that the usage amount of the alkali is higher than 2.5 equivalents relative to that of the azilsartan (2).

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for reducing impurities produced during the preparation of angiotensin II receptor antagonists (ARBs). Background technique [0002] Azilsartan medoxomil, also known as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2' -(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate , angiotensin Ⅱ receptor antagonists (ARBs) developed by Takeda Pharmaceutical Co., Ltd. of Japan are prodrugs of azilsartan (azilsartan) and are used for the treatment of hypertension. The structure is shown in formula (I): [0003] [0004] On February 25, 2011, the US FDA approved the potassium salt of azilsartan medoxomil (trade name Edarbi) for the treatment of hypertension in adults, and clinical studies have confirmed that it has a stable and long-lasting antihypertensive effect. Clinical research data show that compared with the other two FDA-a...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D413/10
CPCC07D413/10C07D413/14
Inventor 左阳黄思娟吴旺江陈万春
Owner 安徽省凤阳县御膳油脂有限公司
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