Set of intermediate compounds used for synthesis of Ivabradine, and applications thereof

Abstract

The invention provides a set of intermediate compounds used for synthesis of Ivabradine and a preparation method thereof, and also provides a method used for synthesizing Ivabradine from the intermediate compounds. According to the method, the set of intermediate compounds are subjected to a plurality of N alkylation or N acylation so as to obtain a compound IV; and Ivabradine is directly synthesized from the compound IV. The method is short in synthesis route; raw materials are simple and easily available; reaction sequence is reasonable; operation is simple and high in efficiency; the method is green and friendly to the environment; synthesis difficulty of Ivabradine is reduced greatly; cost is low; product yield is high; and the method is suitable for industrialization production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a group of novel compounds and their application in the synthesis of ivabradine. Background technique [0002] Ivabradine, chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl] -methylamino]propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one, its structure is shown in the following formula: [0003] [0004] Ivabradine and its pharmaceutically acceptable acid addition salts, especially the hydrochloride, have very important pharmacological and therapeutic properties, especially heart rate slowing properties, which make these compounds useful for prophylactic or therapeutic Various clinical myocardial ischemic conditions, such as angina, myocardial infarction and related rhythm disturbances, represent a very promising new generation of cardiovascular drugs. [0005] At present, the synthesis of ivabradine mainly includes the f...

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Problems solved by technology

[0019] This route is CN102633720A patent (Seville, France), which is an optimization and improvement of the third route of the method. The reaction principle is simple, easy to operate, and avoids the use of toxic reagents in the cyclization step, but the reducing agent for the first step of reductive amination reaction is selected Since sodium triacetoxyborohydride, sodium cyanoborohydride, and catalysts such as palladium, platinum, nickel, nails, germanium and their compounds, the cost is too high, and the starting materials are not easy to obtain, and hydrazine hydrate is required for industrialization. Production pollution is large and the cost is high

[0020] From the existing synthetic methods of ivabradine, it can be seen that no matter which method, the preparation cost of ivabradine is high, the preparation is difficult, the operation is cumbersome and the yield is low, and there is a certain bottleneck in industrial scale-up production

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