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Synthetic method of azilsartan medoxomil or its salt and its intermediate and synthetic method of intermediate

A technology for azilsartan medoxomil and a compound, which is applied in directions such as organic chemistry, can solve problems such as low yield of synthesizing azilsartan medoxomil and many by-products, and achieves the effects of easy purification of finished products and improved reaction yield

Active Publication Date: 2016-01-13
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the above problems, the present invention provides a new method for synthesizing Azilsartan Medoxomil or its salt, which solves the problems of low yield and many by-products in the synthesis of Azilsartan Medoxomil

Method used

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  • Synthetic method of azilsartan medoxomil or its salt and its intermediate and synthetic method of intermediate
  • Synthetic method of azilsartan medoxomil or its salt and its intermediate and synthetic method of intermediate
  • Synthetic method of azilsartan medoxomil or its salt and its intermediate and synthetic method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 1), the preparation of the compound of formula (4)

[0049]

[0050] Add 159g of methanol and 24.2g of the methyl ester compound of formula (5) into a 500mL reactor, stir for 10 minutes, add 10% sodium hydroxide solution dropwise, and heat to reflux for 2 hours. Cool down to room temperature, add 500g of water, adjust the pH value to neutral with 2N hydrochloric acid, precipitate a solid, filter, wash with water, and dry to obtain the compound of formula (4), with a yield of 95.6%.

[0051] 2) Preparation of the compound of formula (3)

[0052]

[0053] Add 48.8g of hydroxylammonium hydrochloride and 81.6g of sodium bicarbonate to 400mL of dimethyl sulfoxide, stir at room temperature for 1 hour, add 16.1g of the compound of formula (4), heat to 90°C for 24 hours, add 800ml of water, and adjust the pH value with 2N hydrochloric acid To neutrality, a solid was precipitated, filtered, washed with water, and dried to obtain the compound of formula (3), with a yield o...

Embodiment 2

[0064]1) Preparation of the compound of formula (4)

[0065]

[0066] Add 159g of methanol and 24.2g of the methyl ester compound of formula (5) into a 500mL reactor, stir for 10 minutes, add 10% sodium hydroxide solution dropwise, and heat to reflux for 2 hours. Cool down to room temperature, add 500g of water, adjust the pH value to neutral with 2N hydrochloric acid, precipitate a solid, filter, wash with water, and dry to obtain the compound of formula (4), with a yield of 95.6%.

[0067] 2) Preparation of the compound of formula (3')

[0068]

[0069] Add 16.2 g of the compound of formula (4) and 8.8 g of potassium carbonate into 200 mL of acetone, slowly add 6.0 g of the compound of formula (6) dropwise, and stir the reaction at room temperature for 10 hours after the addition. The insoluble matter was removed by filtration, and the mother liquor was concentrated to dryness to obtain the compound of formula (3'), with a yield of 86.2%.

[0070] HNMR (300MHz, DMSO-...

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Abstract

The invention relates to the field of medicines and in particular relates to a synthesis method for azilsartan medoxomil or salt thereof, an intermediate of the azilsartan medoxomil or the salt thereof and a synthesis method for the intermediate. According to the novel method for the azilsartan medoxomil or the salt thereof, the problems of low synthesized azilsartan medoxomil yield and large number of byproducts are solved. Furthermore, the invention further provides a synthesis intermediate of the azilsartan medoxomil or the salt thereof and two preparation methods. In a synthesis process, an alcohol fragment of the azilsartan medoxomil is introduced at first, so that a part of the azilsartan medoxomil is formed, and a cyclization structure fragment is synthesized; therefore, the problem that the yield is reduced because of side reaction caused by active hydrogen in a carbonyldimidazole structure of an azilsartan acid structure is solved in a reaction process; the reaction yield is greatly improved, so that a finished product is easier to purify; the synthesis method is particularly suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a synthesis method of azilsartan medoxomil or a salt thereof, an intermediate and a synthesis method of the intermediate. Background technique [0002] Azilsartan medoxomil (INN, code TAK-491) is a selective angiotensin II receptor antagonist with antihypertensive and central nervous effects. It is the prodrug of Azilsartan. On April 28, 2010, the drug developed by Japan's Takeda Pharmaceutical Company (Takeda) completed the Phase III clinical trial. It was approved by the US FDA in 2011. The drug is a vascular tension drug. Candesartan receptor antagonists, which can be used alone or in combination with other antihypertensive drugs, are regarded as the next generation of candesartan cilexetil. [0003] In the prior art, for example, in patents CN1946717, CN102344415 and CN102731491, the preparation of azilsartan medoxomil is as shown in the following formula, firstly prepare azilsartan ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14C07D405/12
CPCC07D405/12C07D413/14
Inventor 叶天健郁光亮张绩生马苏旺
Owner ZHEJIANG YONGNING PHARMA
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