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Synthesis of Azilsartan

Sep 16，2021

Azilsartan, the trade name is Azilva, that is 2-ethoxy-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole- 3-yl)biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylic acid. It is an AT1 subtype angiotensin II receptor antagonist (ARB) developed by Takeda, Japan. It was approved to be marketed in Japan on January 18, 2012. It has now been approved for marketing in the United States and the European Union. Azilsartan, as a new generation of dual-function ARBs, not only antagonizes the type 1 receptor of angiotensin II (AT1 receptor), but may also reduce the risk of cardiovascular disease and diabetes through a variety of mechanisms. Clinical trials have shown that Azilsartan has a good curative effect, a low incidence of adverse reactions, and good compliance.

Preparation

Article illustration

1. Preparation of Azilsartan oxime

Triethylamine (61.8g) was added to the mixed solution of dimethyl sulfoxide (200mL) and hydroxylamine hydrochloride (42.4g), and a large amount of solid precipitated. Filter and wash the filter cake with tetrahydrofuran. The filtrate was concentrated to remove tetrahydrofuran and then added 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester 50.0g, reacted at 75℃ for 15 Hour. After the reaction, it was quenched by adding water, and extracted with ethyl acetate. The organic phase was washed with 1mol/L hydrochloric acid, and the aqueous phase was adjusted to pH 10-11 with 1mol/L sodium hydroxide aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain Azilsartan oxime 29.7 g, the yield is 55%.

2.Preparation of Azilsartan

Add 8.8 g of Azilsartan oxime to 20 ml of 10% sodium hydroxide solution, stir at 50°C for 3 hours, and all are dissolved. Control the temperature at 20-30°C, and add a mixed solution of triphosgene (3.0g)/tetrahydrofuran (15ml) dropwise. After the addition is completed, keep the reaction temperature at 20-30°C, continue the reaction for 2-3 hours, after the reaction is completed, adjust the pH to 2-3, precipitate a white solid, and dry it to obtain azilsartan 7.5g with a yield of 83%.

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