Preparing method and refining method for milrinone
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A refining method and technology of milrinone are applied in the preparation method and refining field of milrinone, and can solve the problems of large amount of solvent, difficult operation, poor product quality, etc., so as to reduce production cost, improve product quality and yield, Easy to use effect
Inactive Publication Date: 2014-03-26
南京易亨制药有限公司
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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.
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Embodiment 1
[0022] Example 1 Milrinone preparation
[0023] In a 150L reactor, add 6.9Kg (56.55mol) of ethoxymethylenemalononitrile and 36Kg of absolute ethanol, stir, and raise the temperature to about 40℃ until all ethoxymethylenemalononitrile is dissolved ; Add 6Kg (44.37mol) 1-(4-pyridyl)-2-acetone in anhydrous ethanol solution dropwise, after dripping, keep for 1.5h, then warm up to 80 ℃ for reflux, keep for 4h, until the reaction is over, stir , The reaction liquid was cooled to 40°C, solid-liquid separation, and solids were collected to obtain 12.9Kg of dark red milrinone crude wet material. The synthesis yield was about 84%.
Embodiment 2
[0024] Example 2 Milrinone's primary purification
[0025] In a 100L reactor, add 12.9Kg of milrinone crude wet material and 39Kg of drinking water, stir, heat up to about 65℃, adjust pH=1 with concentrated HCl, and add 1.29Kg of activated carbon and stir for 5 -10 minutes, filter while hot, collect the filtrate, stir, cool to 0-5°C to crystallize, collect the solid, and obtain 10.8Kg of milrinone primary refined product wet material.
Embodiment 3
[0026] Example 3 Milrinone's secondary purification
[0027] In a 50L reactor, add 10.8Kg of milrinone primary refined product wet material and 33Kg of drinking water, stir, heat up to 80-100℃, until all dissolved, stir, cool to 0-5℃ to crystallize, collect solids, 7.5Kg of milrinone second refined product wet material.
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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 ...
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