Preparation method of high purity ivabradine hydrochloride

Abstract

The invention discloses a preparation method of high purity ivabradine hydrochloride. According to the preparation method, ivabradine hydrochloride is prepared through three steps including nucleophilic substitution, catalytic hydrogenation, and hydrochloride formation. A bicarbonate solution is adopted to wash a dehydro ivabradine solution to remove most unreacted compound II, so that column chromatography operation is avoided, operation is simple; normal pressure hydrogenation is adopted, so that using of a high pressure hydrogenation kettle is avoided, blocking of condensers is avoided, andoperation is safe; the purity of obtained ivabradine hydrochloride is 99.8%, the content of the highest single impurity is less than 0.10%, bulk drug standards can be reached without refining; and areaction route is disclosed in the invention.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular, the invention relates to a method for preparing ivabradine, in particular to a method for preparing ivabradine hydrochloride. Background technique [0002] Ivabradine hydrochloride, its chemical name is 3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]oct-1,3,5-triene]methanol Base-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepine -4-Kone hydrochloride, the structural formula is as follows [0003] [0004] Ivabradine hydrochloride is an If inhibitor, which is used to treat chronic stable angina symptoms in patients with normal sinus rhythm who are contraindicated or intolerant to β-receptor blockers. It is a new generation of cardiovascular drugs with very broad treatment prospects drugs. [0005] Many patents disclose ivabradine hydrochloride, its preparation method and the preparation of key intermediates. These patents include: EP534859, US5296482, FR199100...

AI Technical Summary

Problems solved by technology

[0008] This method is the mainstream route for preparing ivabradine at present. The disadvantage is that starting from dehydroivabradine, the hydrogenation reaction uses high-pressure hydrogen to pressurize, which requires high production equipment; Column purification is required before and after the reaction, the amount of organic solvent is large, the yield is low, the process cost is high, and it is difficult to realize industrial production

[0009] Chinese patent CN103012268A describes a method for preparing ivabradine using the same synthetic route, which improves the hydrogenation reaction, uses palladium carbon as a catalyst, ammonium formate as a hydrogen donor, and hydrogenation at normal pressure solves the problem of using high pressure in industry However, the ammonium bicarbonate produced when ammonium formate is thermally decomposed will sublimate, which will cause the blockage of the condenser, which is very dangerous and unfavorable for industrial safety production; and the purity of its product is only 98.5%, which is not enough to meet the requirements of raw materials. standard

[0010] The main reason for the low purity is that compound II cannot react completely during the reaction process, and compound II is chemically similar to compound III and compound IV, and it is difficult to remove it without post-processing of column chromatography

Images