Synthesis method of milrinone

Abstract

The invention discloses a synthesis method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is taken as a raw material to react with alpha-(N, N-dimethylamine methylene) malononitrile, so as to obtain an off-white solid milrinone. The method for synthesizing milrinone is simple and convenient to operate, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of milrinone. Background technique [0002] Milrinone, also known as cyanopyridone, its CAS number is: 78415-72-2, is 1,6-dihydro-2-methyl-6-oxo-[3,4'-linked The general name of pyridine]-5-carbonitrile was first successfully developed by Sterling Company of the United States. It was first approved by the FDA in the United States in 1987 and officially listed in the United States in 1992. It was subsequently sold in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries. It is marketed in Brazil and other countries, and its lactate is used clinically. It is mainly suitable for the treatment of refractory heart failure and heart failure patients with digitalis poisoning. Recent studies have shown that milrinone can also be used for low cardiac output after extracorporeal circulation in cardiac surgery. Syndrome,...

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Problems solved by technology

[0006] 一种方法是采用“直线式”合成路线(如US4469871A,US4413127A,EP0095152,US4313951A,J.Med.Chem.,1986,29,635-640,CN103288725B,CN104387320B,CN1253439C,CN106243032A,CN105777626A,CN104526975A,CN101143844A等): With 4-picoline as the starting material, 1-(4-pyridyl)-2-propanone is prepared. This step reaction can be realized through two paths. The first path is to use n-butyllithium or phenyllithium It reacts with ethyl acetate under certain conditions, but the reaction conditions are harsh, and the requirements for water are strict. It is easy to produce exothermic reaction when it encounters water and oxygen, and it is easy to burn in the air. Once it is heated, it will easily cause explosion. More expensive, and there is a risk of generating toxic benzene during the reaction, so it is not suitable for industrial production

The second path is to react with acetyl chloride at room temperature for 16 hours. Although the reaction conditions are mild, the reaction time is too long

[0013] (1) The milrinone prepared by the existing milrinone synthesis method is not high in purity and red in color, and it is difficult to achieve the predetermined effect through further refining means

[0014] (2) In the synthesis process of milrinone, there are generally longer reaction steps, which cause the overall yield to be low

[0015] (3) The synthetic route of existing milrinone is relatively complicated, and reaction conditions are harsh, and some need to apply highly toxic potassium cyanide or malononitrile, which makes the process operation less safe and industrialized production is more difficult to realize

[0016] Summarizing the many problems existing in the prior art, it is still a problem to be solved at present to study and find a mild reaction condition, simple operation process, high product yield, high purity, and low production cost suitable for industrialized production of milrinone.

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