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Preparation method of azilsartan

A compound and reaction technology, applied in the field of drug synthesis, can solve the problems of unfavorable industrial production, long process route, and many by-products, and achieve the effects of shortening post-processing time, avoiding by-products, and improving reactivity

Inactive Publication Date: 2018-10-16
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Ethyl chloroformate and hydrazine hydrate are used in the above-mentioned synthetic route, all are poisonous and harmful reagents, cause potential safety hazard in the production process, there are many by-products in the reaction process, and the process route is too long, so it is not conducive to large-scale industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Add 19.76kg (235.0mol) of sodium bicarbonate and 12.24kg (176.3mol) of hydroxylamine hydrochloride into 110.kg of DMSO, stir and raise the temperature to 50-60°C, stir for 1 hour, and add 25.04kg (58.8mol) of the compound to the above reaction solution 5. Raise the temperature to 75-85°C, keep stirring and react for 7-10 hours. After the reaction, the reaction solution was added to 200.16kg of purified water, stirred at 20-30°C for 1 hour, centrifuged, and the filter cake was rinsed with 12.24kg of purified water and dried to obtain 22.23kg of compound 6 with a yield of 82.5%.

[0047] Add 22.10kg (48.2mol) of compound 6 and 12.50kg (77.1mol) of carbonyldiimidazole into 146.41kg of dichloromethane, stir to dissolve, control the temperature at 25-30°C, add 9.73kg (100.9mol) of triethylenediamine and 87.85kg of dichloromethane mixed solution, reacted at 25~30°C for 2~3h, after the reaction was complete, adjusted pH=3 with 196.52kg of 1N hydrochloric acid, discarded the aq...

Embodiment 2

[0051] Add 29.43kg (350.3mol) of sodium bicarbonate and 20.42kg (293.8mol) of hydroxylamine hydrochloride into 110.kg of DMSO, stir and raise the temperature to 50-60°C, stir for 1 hour, and add 25.00kg (58.8mol) of the compound to the above reaction solution 5. Raise the temperature to 75-85°C, keep stirring and react for 7-10 hours. After the reaction, the reaction solution was added to 200.16kg of purified water, stirred at 20-30°C for 1 hour, centrifuged, and the filter cake was washed with 12.24kg of purified water and dried to obtain 21.84kg of compound 6 with a yield of 81.1%.

[0052] Add 21.80kg (47.5mol) of compound 6 and 26.98kg (166.4mol) of carbonyldiimidazole into 146.41kg of dichloromethane, stir to dissolve, control the temperature at 25-30°C, add 21.33kg (190.2mol) of triethylenediamine and 87.85kg of dichloromethane mixed solution, reacted at 25-30°C for 2-3 hours, after the reaction was complete, adjusted pH=3 with 410.61kg of 1N hydrochloric acid, discarded t...

Embodiment 3

[0056] Add 14.81kg (176.3mol) of sodium bicarbonate and 8.17kg (117.5mol) of hydroxylamine hydrochloride into 110.kg of DMSO, stir and raise the temperature to 50-60°C, stir for 1 hour, and add 25.00kg (58.8mol) of the compound to the above reaction solution 5. Raise the temperature to 75-85°C, keep stirring and react for 7-10 hours. After the reaction, the reaction solution was added to 200.16kg of purified water, stirred at 20-30°C for 1 hour, centrifuged, and the filter cake was rinsed with 12.25kg of purified water and dried to obtain 19.93kg of compound 6 with a yield of 74.0%.

[0057] Add 19.80kg (43.2mol) of compound 6 and 8.40kg (51.8mol) of carbonyldiimidazole into 146.41kg of dichloromethane, stir to dissolve, control the temperature at 25-30°C, add 7.27kg (64.8mol) and 87.85kg of dichloromethane Methane mixture, react at 25-30°C for 2-3 hours, after the reaction is complete, use 176.1kg 1N hydrochloric acid to adjust pH=3, discard the water phase after liquid separ...

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Abstract

The invention belongs to the field of drug synthesis. A preparation method of azilsartan is characterized by comprising the following steps that 1) a compound 5 reacts with hydroxylamine hydrochlorideunder the alkaline condition to generate a compound 6 by heating reaction; 2) the compound 6 reacts under the action of carbonyl diimidazole under triethylene diamine to generate a compound 4; 3) thecompound 4 generates hydrolysis reaction under the alkaline condition to obtain a crude azilsartan product; 4) the crude azilsartan product is refined to obtain the azilsartan. The preparation methodof the azilsartan has the advantages of short reaction time, high product purity and high yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention specifically relates to a preparation method of azilsartan, which belongs to the field of drug synthesis. Background technique [0002] Azilsartan, chemical name: 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) phen-4-yl]methyl]benzimidazole-7-carboxylic acid. Developed by Takeda Corporation of Japan and approved for marketing in Japan in January 2012, it can antagonize the binding of angiotensin II to angiotensin II receptors. Strong inhibition of vasoconstriction reduces peripheral vascular resistance, resulting in a hypotensive effect. The specific structure 1 is as follows: [0003] [0004] There are many synthetic routes of azilsartan, for example: the patent US5243054 uses compound 2 as the starting material and ethyl chloroformate under the action of DMP to generate compound 3, compound 3 reacts with hydroxylamine hydrochloride under the condition of sodium methoxide as the base to generate compound 4. Compound 4 w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 郑士彬赵寅宝王辉胡卫东
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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