Novel preparation method of azilsartan medoxomil sylvite and its intermediate

Abstract

The invention relates to a novel preparation method of azilsartan medoxomil sylvite and its intermediate. The method comprises the following steps: hydrolyzing a starting material VII to obtain an intermediate IX, then performing esterification with a side chain IV to obtain the intermediate X; reducing the other starting material VIII by hydroxylamine hydrochloride to obtain the intermediate XI, then performing esterification with ethyl chloroformate to obtain the intermediate XII, and closing ring to obtain the intermediate XIII; performing condensation of the intermediate X and the intermediate XIII to obtain the intermediate II, and finally performing reaction with potassium isooctanoate to obtain the azilsartan medoxomil sylvite. The method has the advantages of easy acquisition of raw materials, short synthesis route, less equipment investment, less by-product, low toxicity, little pollution, environment protection, and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a new preparation method for preparing an intermediate of azilsartan medoxomil potassium salt and azilsartan medoxomil potassium salt. Background technique [0002] Hypertension is a chronic disease characterized by continuous elevation of arterial blood pressure, which often causes lesions in heart, brain, kidney and other important organs with corresponding consequences. It is the most important risk factor for cardiovascular and cerebrovascular diseases, and stroke, heart failure and chronic kidney disease are its main complications. Reducing the blood pressure level of hypertensive patients can significantly reduce stroke and heart disease events, significantly improve the quality of life of patients, and effectively reduce the burden of disease. Because some hypertensive patients have no obvious clinical symptoms, hypertension is also known as the "invisi...

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Problems solved by technology

There are also the following problems: (1) When the cyano group is reduced with hydroxylamine, the temperature is relatively high (115~120°C), and the 2-position ethoxy group is easy to break the bond during the reaction, dropping the ethyl group, resulting in an increase in impurities; (2) 7-position The hydroxyl groups on the carboxyl group and the amidino group are easy to react with the side chain (IV), thereby introducing impurities and reducing the yield; (3) the temperature of the oxazole ring ring is very high (110°C or 140°C), and the 7-position has formed The ester bond is easily broken, resulting in low yield; (4) a relatively high price is used in the cyclization N,N -Carbonyldiimidazole reagent, resulting in relatively high cost of raw materials, not suitable for industrial production

[0037] In short, route 2 is a route of little practical significance in industry. After azilsartan is first esterified, there will be more side reactions on the oxazole ring in the actual reaction, because the methyl ester at the 7th position of the intermediate is hydrolyzed. The exposed carboxylic acid and the hydroxyl group on the amidine group after the reduction of the cyano group have strong activity, and corresponding side reactions are likely to occur simultaneously in both esterification and cyclization, resulting in more impurities, lower yields, and increased costs.

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