Preparing method and refining method for milrinone

Abstract

The invention relates to a preparing method and a refining method for milrinone. The preparing method comprises the following steps: an absolute ethyl alcohol solution of 1-(4-pyridyl)-2-acetone is added dropwise into an absolute ethyl alcohol solution of ethoxymethylenemalononitrile, heat preservation is performed for 1-3 h under a condition of 20 DEG C-60 DEG C, then the temperature is increased to 75 DEG C-85 DEG C, a reaction liquid is cooled to 0-50 DEG C after a reaction is completed, solid-liquid separation is performed, and a solid is collected to obtain a product, wherein the mass ratio of ethoxymethylenemalononitrile to 1-(4-pyridyl)-2-acetone is (1.5-3):(1.5-2.5). According to the preparing method and the refining method, water is adopted to replace a purification solvent such as DMF (dimethyl formamide), methanol, ethanol and the like, so that not only are impurities removed effectively, all single impurities in a finished milrinone product is smaller than 0.1%, and solvent residues reach the standard, but also the production cost is reduced, product quality and yield are improved, and the methods are suitable for industrial production.

Description

Technical field [0001] The invention relates to the technical field of compound preparation, in particular to a preparation method and a refining method of milrinone. Background technique [0002] Milrinone (the structure is shown in formula I) is also known as cyanpyridone and its chemical name is 1,6-dihydro-2-methyl-6-oxy-[3,4bispyridine]-5-carbonitrile, It is a non-digital cardioside and non-catecholamine positive inotropic drug that selectively inhibits phosphodiesterase III in myocardial cells, changes the transport of calcium ions inside and outside the cells, enhances myocardial contractility, and has vasodilators It is used to treat congestive mental failure. [0003] [0004] The existing milrinone preparation methods and refining methods have defects such as poor product quality, and the appearance of milrinone agricultural products is yellow or light yellow, and it is difficult to meet the quality requirements of injections. [0005] Literature 1 (Zheng Xiaozhang, Feng ...

AI Technical Summary

Problems solved by technology

[0004] The existing milrinone preparation methods and refining methods have defects such as poor product quality, and the appearance of milrinone products is yellow or light yellow, which is difficult to meet the quality requirements of injections

[0005] Document 1 (Zheng Xiaozhang, Feng Zixia, Liu Yisun. Synthesis of cardiac drug milrinone [J]. China Pharmaceutical Industry Journal, 1990, 21(11): 486-488) and Document 2 (Xu Fang, Ren Jinhe, Chen Jiandong, Liao Qingjiang, the synthesis of milrinone [J]. Journal of China Pharmaceutical University, 1996, 27 (6): 377-378) discloses the refinement method of milrinone, this method adopts DMF recrystallization purification milrinone, because Milrinone is easy to decompose at high temperature, and the DMF residue in the refined product of milrinone is large and cannot be removed, which cannot meet the quality requirements of injection

[0006] Document 3 (Liu Qiming, Su Yuyong, Chen Bangyin, Zhang Hanping. Synthesis and structural identification of phosphodiesterase inhibitor Milrinone [J]. Journal of Huazhong University of Science and Technology (Medical Science), 2005, 34(1): 74-75) published A refining method for milrinone is proposed, which uses ethanol recrystallization to purify milrinone. This method has defects such as large solvent consumption, high purification cost, difficult operation, poor impurity removal effect, and unsuitability for industrial production.

Images