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Preparation method of azilsartan

A technology of azilsartan medoxomil and microreactor, which is applied in the fields of chemical instruments and methods, chemical/physical/physical chemical processes, organic chemistry, etc., and can solve unfavorable industrial production, deethylated impurities, unfavorable environmental protection, etc. problems, to achieve the effect of continuity and automation, less by-products, and easy separation and purification

Active Publication Date: 2017-08-18
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

[0010] The main defect in the above two methods is that there are many deethylated impurities generated in the ring-closing reaction, which are difficult to drop to below 0.1% through refining, and the yield of qualified azilsartan obtained through repeated refining is also extremely low. The process is cumbersome and the cost is high, which is not conducive to industrial production
In addition, a large amount of organic solvents are used in the whole synthesis, which is not conducive to environmental protection

Method used

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  • Preparation method of azilsartan
  • Preparation method of azilsartan
  • Preparation method of azilsartan

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Embodiment 1

[0032] Such as figure 1 As shown, the microreactor of the present invention includes a temperature control unit and a reaction unit such as figure 1 Connect to install. The compound 2 solution and carbon dioxide enter the temperature control unit of the microreactor respectively, control the temperature at 90-120°C, and then control the pressure at 0.8-1.2MPa. After the two solutions are mixed and reacted in the reaction unit for 48-480S, they exit the microreactor Proceed to the next step.

Embodiment 2

[0033] The preparation of embodiment 2 Azilsartan

[0034] Dissolve 45g (0.1mol) of compound 2 (methyl ester) in 450ml of dimethyl sulfoxide, and control the flow rate of 40ml / min and flow rate of 1L / min respectively with carbon dioxide into the microreactor, and control the temperature by the temperature control unit to 90-100 After ℃, in the reaction unit at 90-100 ℃, keep the pressure of 1.0MPa and react for 120 seconds. Azilsartan methyl ester solution was obtained from the microreactor through a gas-liquid separator, added to 450ml of 1mol / L sodium hydroxide aqueous solution, stirred and reacted at a temperature of 20-30°C for 2h, added 450ml of toluene, and adjusted to pH=3 with hydrochloric acid -5, liquid separation, subtractive evaporation to remove toluene, add 400ml of ethanol, dissolve, cool down and crystallize, filter and dry to obtain 42.6g of white solid with a yield of 93.4% and a purity of more than 99.8% by HPLC.

[0035] ESI (+) MS = 457.1.

[0036] 1 HN...

Embodiment 3

[0037] The preparation of embodiment 3 Azilsartan

[0038] Dissolve 45g (0.1mol) of compound 2 (methyl ester) in 450ml of N,N-dimethylformamide, and control the flow rate of 40ml / min and 1L / min respectively with carbon dioxide into the microreactor. In the reaction unit at 90-100°C, keep the pressure of 1.0 MPa for 120 seconds. Azilsartan methyl ester solution was obtained from the microreactor through a gas-liquid separator, added to 450ml of 1mol / L sodium hydroxide aqueous solution, stirred and reacted at a temperature of 20-30°C for 2h, added 450ml of toluene, and adjusted to pH=3 with hydrochloric acid -5, liquid separation, subtractive evaporation to remove toluene, add 400ml of ethanol, dissolve, cool down and crystallize, filter and dry to obtain 42.2g of white solid with a yield of 92.5% and a purity of more than 99.8% by HPLC. ESI (+) MS = 457.1.

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Abstract

The invention discloses a preparation method of azilsartan. The method comprises the following steps: introducing an organic solvent solution of a compound 2 and carbon dioxide gas into a micro reactor, mixing and reacting at the temperature of 90 to 120 DEG C under the pressure of 0.8 to 1.2Mpa for 48 to 480 seconds to obtain azilsartan medoxomil, and discharging the azilsartan medoxomil out of the micro reactor; then, performing alkaline hydrolysis to obtain the azilsartan. A synthetic method disclosed by the invention has the advantages of use of readily-available raw materials, easiness in operation, less reaction side products in each step, high yield, extremely high purity of an obtained product, easiness in separating and purifying reaction products in each step, and suitability for industrial production. The structure of the azilsartan is shown in the description.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of azilsartan. Background technique [0002] The chemical name of Azilsartan is: 2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3- Base) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, molecular formula: C 25 h 20 N 4 o 5 , molecular weight: 456.45, structural formula: [0003] [0004] Azilsartan was developed and produced by Takeda Corporation of Japan, and was first launched in Japan in January 2012. Azilsartan is an angiotensin Ⅱ receptor antagonist sartan drug, which has a significant clinical effect in the treatment of adult hypertension. It was developed by Japan's Takeda Pharmaceutical Company (Takeda), and it was launched in Japan in 2012. Used alone or in combination with other antihypertensive drugs, it is regarded as the next generation product of candesartan cilexetil. It is superior to the clini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10B01J19/00
CPCB01J19/0093C07D413/10
Inventor 周先国杨庆坤常宝磊陈中南李德才吴柯董廷华
Owner 山东安信制药有限公司
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