Ibutilide fumarate synthetic process

Abstract

The invention relates to a process for synthesizing ibutilide fumarate. 2-pyrrolidone is taken as an initial raw material, DMF is taken as a solvent, and the 2-pyrrolidone and the DMF are N-alkylated with halogen ethane to obtain N-ethyl-butyrolactam under the catalysis; then 4-ethylamino-ethyl acetic acid is obtained through acid hydrolysis; the 4-ethylamino-ethyl acetic acid reacts with chloroheptane under the catalysis to obtain 4-ethylheptylamino-ethyl acetic acid; 4-ethylheptylamino-n-butyryl chloride is obtained through the acidylation; and the 4-ethylheptylamino-n-butyryl chloride is subjected to friedel-crafts reaction with N-phenylmethanesulfonamide to obtain (+ / -)-N-[4-[4-(ethylheptylamino)-1-ketonebutyl]phenyl] methanesulfonamide, (+ / -)-N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl] methanesulfonamide is obtained by reducing sodium borohydride and / or tetrahydro-aluminate lithium, and then a target compound, namely the tetrahydro-aluminate lithium is obtained by salifying with fumaric acid. The process is more reasonable and is more convenient for industrialized production.

Description

Technical field: [0001] The invention relates to a new synthesis process of ibutilide fumarate Background technique: [0002] The new antiarrhythmic drug ibutilide fumarate (Ibutilide fumarate) is a fast-acting and safe class III antiarrhythmic drug, especially for the rapid termination of atrial flutter and atrial fibrillation. The chemical name of ibutilide fumarate is (±)-N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide fumarate, which is A new type of ion antagonist antiarrhythmic drug developed by Upjohn Company of the United States, which was first launched in the United States in 1996. Ibutilide fumarate is also the first intravenous application approved by the FDA in the United States for the treatment of atrial flutter and atrial fibrillation. The drug, whose trade name is Convert, has been marketed in 11 countries including Germany, and its clinical injection is mainly used for the conversion of atrial fibrillation and atrial flutter. At presen...

AI Technical Summary

Problems solved by technology

[0011] The comparison of the three methods, the first method is an older preparation method, but there is no industrial production of methanesulfonanilide in China, and the yield is low

In method two, pyridine, which is more toxic and difficult to handle, is used as a binding agent for the acid. In the third step of method two, 1-hydroxybenzotriazole, which is more toxic and difficult to handle, is used as a catalyst. Imine is a shrinking agent, and the obtained product amide is not easy to handle, and the overall yield is not high

Generally speaking method three is better, and raw material is easy to get, and overall yield is higher, is suitable for industrialized production, but the diisopropylcarbodiimide (DIC), N-ethylheptylamine and The reductant lithium aluminum tetrahydrohydride (2,000,000.00 yuan / ton) for the final hydrogenation reduction is relatively expensive, and the hydrogenation reduction of N-ethyl-N-heptyl 4-oxo-4-(4-methanesulfonamidophenyl)butyramide For Ibutilide, two carbonyl groups need to be reduced, that is, it takes twice as much Lithium Aluminum Hydride, resulting in high synthesis cost

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