A kind of synthetic method of azasetron hydrochloride

Abstract

The invention provides an azasetron hydrochloride synthesis method. The azasetron hydrochloride synthesis method comprises the following steps of: preparing a C10H8ClNO4 crude product, namely an azasetron hydrochloride midbody crude product, by using 6-chlorine-4-methyl-3, 4-dihyro-3-oxo-2H-1, 4-benzoxazine-8-carboxylic acid methyl ester, sodium hydroxide, absolute ethyl alcohol, water and hydrochloric acid,; refining the azasetron hydrochloride midbody crude product by using the absolute ethyl alcohol so as to prepare an azasetron hydrochloride midbody refined product; reacting the azasetron hydrochloride midbody refined product with 3-amion quinine amine hydrochloride, triethylamine, N-hydroxy succinimide, N, N'- dicyclohexylcarbo-diimide and trichloromethane so as to prepare an azasetron hydrochloride crude product; and refining the azasetron hydrochloride crude product by using the absolute ethyl alcohol so as to prepare the azasetron hydrochloride. The azasetron hydrochloride synthesis method has the advantages of short synthesis route, environmental protection, high yield, easiness in operation and the like. Compared with a conventional method, the azasetron hydrochloride synthesis method can be used for increasing the yield by about one time.

Description

technical field [0001] The invention relates to the field of medicine, more specifically a method for synthesizing azasetron hydrochloride. Background technique [0002] Azasetron Hydrochloride (AzasetronHydrochloride, Y-25130) is mainly suitable for the treatment of gastrointestinal symptoms such as nausea and vomiting caused by taking anti-cancer drugs (cisplatin, etc.), and is a highly efficient, highly selective, safe to use, 5-HT3 receptor antagonist with low side effects. [0003] The synthetic method of azasetron hydrochloride generally adopts 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid through chlorination It can be prepared by reacting with 3-aminoquinuclidine hydrochloride to form a salt, and its route is: [0004] [0005] In scheme A, thionyl chloride is used to react with the hydrolyzate to generate acid chloride and then amide to generate azasetron. The technical scheme is to use 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benz...

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Problems solved by technology

[0005] In scheme A, thionyl chloride is used to react with the hydrolyzate to generate acid chloride and then amide to generate azasetron. The technical scheme is to use 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid methyl ester and sodium hydroxide to react with dilute Hydrochloric acid to adjust the pH value to obtain 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, and then dichloromethane, chlorine The sulfoxide was mixed and dimethylformamide (DMF) was added dropwise, and then the chloroform solution containing 3-aminoquinuclidine hydrochloride was added after stirring and heating, and the sodium carbonate solution was added after the solid was precipitated, and the white solid was washed with Dissolving in ethanol, filtering, adding concentrated hydrochloric acid to adjust the pH value, standing for crystallization, suction filtration to obtain azasetron hydrochloride, the yield prepared by this method is about 37%, and the yield is relatively low. Environmental pollution is also relatively large; method B requires reaction at -20°C and separation and purification by column chromatography, which is not suitable for scale-up production

At the same time, both method A and method B have the problem that the route is long and difficult to operate

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