Synthesis and refining method of levosimendan
By simplifying the synthetic route of levosimendan and using phase transfer catalysis and green solvents, the problems of numerous steps, low purity, and low yield in existing technologies have been solved, enabling industrial production with high purity and high yield.
Patent Information
- Application Number
- CN202411529986.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-02-11
AI Technical Summary
Existing methods for synthesizing levosimendan involve numerous steps, long cycles, large solvent consumption, severe equipment corrosion, and require improvements in purity and yield. Furthermore, the raw materials are expensive or hazardous, making them unsuitable for industrial production.
Using N-[4-(2-bromopropionyl)phenyl]acetamide as a raw material, it reacts with diethyl malonate in a phase transfer catalytic system. After hydrolysis, decarboxylation, condensation, chiral resolution, and diazotization, it is finally condensed with malononitrile. The purification is carried out using green and environmentally friendly solvents to improve purity and yield.
It simplifies the synthesis route, reduces production costs, improves the purity and yield of levosimendan, is suitable for industrial production, and the solvent is readily available, easy to handle, and environmentally friendly.
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Figure CN119409643A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical chemical industry, in particular to a synthesis and purification method of levosimendan. Background Art
[0002] Levosimendan, chemical name is (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]-hydrazono]-malononitrile, chemical formula is C 14 H 12 N6O, a yellow crystalline powder. Levosimendan is a calcium sensitizer, first developed by Orion Corporation of Finland and first marketed in Sweden in 2000. In the 1980s, a new class of cardiotonic drugs was discovered during the study of drugs for the treatment of congestive heart failure (CHF). This class of drugs mainly works by increasing the responsiveness of myocardial contractile proteins to Ca 2+ The sensitivity of calcium is increased, so it is called calcium sensitizer. 2+ The release of calcium reduces the energy demand of the heart, so it is believed that it can avoid arrhythmias, myocardial cell damage and even death caused by positive inotropic drugs. Studies have shown that calcium sensitizers can reverse myocardial contractile dysfunction under pathological conditions such as acidosis and temporary myocardial disorders. Anti-heart failure drugs with multi-target effects such as Levosimendan.
[0003] Clinical studies have shown that levosimendan can reduce the mortality rate of heart failure by 43%; various clinical trials have shown that levosimendan can improve hemodynamics, improve arrhythmia, chest pain and other related symptoms, and shorten hospitalization time. It has few interactions with other cardiovascular drugs, does not affect the use of other drugs (heart failure patients often need to use a large number of different drugs for simultaneous treatment), and has good safety. Compared with the currently commonly used acute heart failure treatment drugs such as dobutamine and milrinone, it has obvious advantages. Therefore, the synthesis research of levosimendan is of great significance.
[0004] Currently, there are few reports on the synthesis of levosimendan. Although the product can be synthesized through the reaction, either the raw materials used are relatively expensive or the post-processing is relatively complicated, which is not suitable for industrial production.
[0005] In 2006, Meng Fanhao et al. described a synthetic route for levosimendan in "Synthesis of a New Anti-heart Failure Drug Levosimendan". This route uses acetanilide as the starting material and synthesizes a new anti-heart failure drug levosimendan through 7 steps of Friedel-Crafts reaction, bromination, condensation, decarboxylation, cyclization, splitting, and diazotization condensation. This route has many steps, a long cycle, a large amount of solvent, and the use of bromine, which is highly corrosive to the equipment. At the same time, the purity and yield of the obtained levosimendan need to be improved. The synthetic route is as follows:
[0006]
[0007] In 2011, Lisheng Wang et al. described a synthetic route for synthesizing levosimendan analogs in Synthesis and anti-congestive heart failure activity of novel levosimendan analogues. The route uses acetanilide as the starting material and synthesizes levosimendan analogs through 9 steps of Friedel-Crafts reaction, bromination, condensation, decarboxylation, cyclization, splitting, and diazotization condensation. The route has many steps, a long cycle, a large amount of solvent, and the use of bromine, which is highly corrosive to equipment. The synthetic route is as follows:
[0008]
[0009] In 2014, Sun Jinrui et al. described a synthetic route for levosimendan in "Improvement of Levosimendan Synthesis Process". This route uses N-[4-(2-chloropropionyl)phenyl]acetamide as the starting material, and synthesizes the new anti-heart failure drug levosimendan through condensation, decarboxylation, cyclization, splitting, diazotization and condensation in five steps. This route has many steps, a large amount of solvent, and copper powder is used, which is harmful to the environment. At the same time, the purity and yield of the obtained levosimendan need to be improved. The synthetic route is as follows:
[0010]
[0011] Chinese patent CN104418810 uses 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone as the starting material, and reacts with malononitrile to obtain levosimendan after chiral resolution. The raw materials used in this method are expensive, and the purity and yield of the obtained levosimendan need to be improved.
[0012] Chinese patent CN104987310 uses acetanilide and 2-chloropropionyl chloride as starting materials and obtains levosimendan through multiple steps of reaction. This method not only uses aluminum trichloride, which is relatively dangerous, but also uses metallic sodium, which increases the risk of the reaction. At the same time, the purity and yield of the obtained levosimendan need to be improved. Summary of the invention
[0013] The technical problem to be solved by the present invention is: to overcome the deficiencies in the prior art and provide a method for synthesizing and refining levosimendan. The present invention uses N-[4-(2-bromopropionyl)phenyl]acetamide as a raw material, reacts with diethyl malonate under a phase transfer catalysis system to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1), intermediate 1 is dissolved in an acidic solvent, and undergoes a hydrolysis decarboxylation reaction to obtain 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2), then intermediate 2 undergoes a condensation reaction with hydrazine hydrate to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3), intermediate 3 is subjected to chiral resolution using L-tartaric acid to obtain intermediate 4, and finally intermediate 4 is further condensed with malononitrile to obtain levosimendan, and the present invention can improve the purity and yield of levosimendan. The specific preparation route is as follows:
[0014]
[0015] The technical solution adopted by the present invention to solve its technical problem is:
[0016] A method for synthesizing and refining levosimendan, comprising the following steps:
[0017] Step a, synthesis of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1),
[0018] N-[4-(2-bromopropionyl)phenyl]acetamide is used as a raw material, dissolved in a first solvent, and reacted with diethyl malonate in the presence of a phase transfer catalyst system. After a reaction time t1, a reaction system I is obtained. Then, the reaction system I is subjected to a first post-treatment to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1). The chemical reaction formula is as follows:
[0019]
[0020] Step b, synthesizing 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2), dissolving the diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1) obtained in step a in a second acidic solvent, and undergoing a hydrolysis and decarboxylation reaction, and obtaining a reaction system II after a reaction time t2, and then the reaction system II undergoes a second post-treatment to obtain 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2), and the chemical reaction formula is as follows:
[0021]
[0022] Step c, synthesis of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 3),
[0023] The 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2) obtained in step b is dissolved in a third solvent and reacted with hydrazine hydrate for cyclization. After reaction time t3, a reaction system III is obtained. The reaction system III is subjected to a third post-treatment to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3). The chemical reaction formula is as follows:
[0024]
[0025] Step d: chiral separation to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 4).
[0026] The 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3) obtained in step c is dissolved in a fourth solvent and reacted with L-tartaric acid. After reaction time t4, a reaction system IV is obtained. The reaction system IV is subjected to a fourth post-treatment to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 4). The chemical reaction formula is as follows:
[0027]
[0028] Step e: condensation to obtain levosimendan,
[0029] The (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 4) obtained in step d is dissolved in the fifth acidic solvent to obtain reaction system V, then cooled, and subjected to diazotization reaction with nitrite, and after reaction time t5, reaction system VI is obtained, and malononitrile solution is slowly added dropwise at low temperature, and then after reaction time t6 at room temperature, reaction system VII is obtained, and then reaction system VII is subjected to the fifth post-treatment to obtain crude levosimendan; and then the crude levosimendan is refined with a refined liquid to obtain finished levosimendan, and the chemical reaction formula is as follows:
[0030]
[0031] Furthermore, in step a, the phase transfer catalytic system consists of a phase transfer catalyst and an inorganic salt;
[0032] The mass ratio of the N-[4-(2-bromopropionyl)phenyl]acetamide to the first solvent is 1:(3-10); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the phase transfer catalyst is 1:(0.1-0.5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the inorganic salt is 1:(2-5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to diethyl malonate is 1:(1.1-1.5); the reaction temperature is 70-90°C, and the reaction time t1 is 8-12h.
[0033] Furthermore, in step a, the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide (TBAB), tetrahexylammonium bromide (THAB), and tetrabutylammonium iodide (TBAI); the inorganic salt is selected from one or more of potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), and dipotassium hydrogen phosphate (K2HPO4); and the first solvent is selected from one or more of acetonitrile (CH3CN), 1,2-dichloroethane (DCE), and isopropyl alcohol (i-PrOH).
[0034] Furthermore, in the step b, the molar ratio of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate to the second acidic solvent is 1:(20-30); the reaction temperature of the hydrolysis decarboxylation reaction is 80-100° C., and the reaction time t2 is 8-12 h;
[0035] In the step b, the second acidic solvent is selected from one or more of hydrogen chloride-isopropanol solution (HCl-i-PrOH), hydrochloric acid solution (HCl-H2O), and hydrogen chloride-ethanol solution (HCl-EtOH); the molar concentration of the second acidic solvent is 4 mol / L to 9 mol / L.
[0036] Further, in the step c, the mass ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to the third solvent is 1:(10-15); the molar ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to hydrazine hydrate is 1:(1.5-4); the cyclization reaction temperature is 80-100° C., and the reaction time t3 is 2-4 hours;
[0037] In the step c, the third solvent is selected from one or more of ethanol (EtOH), purified water (H2O), and isopropanol (i-PrOH); and the concentration of hydrazine hydrate is 80-85 wt%.
[0038] Further, in the step d, the mass ratio of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to the fourth solvent is 1:(40-60); the molar ratio of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to L-tartaric acid is 1:(1.5-2); the reaction temperature after dissolution is 70-80°C, and the reaction time t4 is 2-4h;
[0039] In the step d, the fourth solvent is selected from one or more of ethanol (EtOH), 1,4-dioxane, and isopropanol (i-PrOH).
[0040] Furthermore, in the step e, the mass ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to the fifth acidic solvent is 1:(50-60);
[0041] In the step e, the reaction system V is cooled to -5 to 5°C, and a nitrite solution is slowly added dropwise; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to nitrite is 1:(1.5 to 2.0), and the reaction time t5 is 1.5 to 3h; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to malononitrile is 1:(1.2 to 1.5);
[0042] In the step e, the temperature of adding the reaction system VI is 0-5°C, and the malononitrile solution is slowly added dropwise; the reaction time t6 is 3-5h;
[0043] In the step e, the fifth acidic solvent is selected from one or more of hydrochloric acid solution (HCl-H2O), sulfuric acid solution (H2SO4-H2O), and phosphoric acid solution (H3PO4-H2O); the nitrite is selected from one or more of sodium nitrite (NaNO2), potassium nitrite (KNO2), and calcium nitrite (Ca(NO2)2); and the refined liquid is selected from one or more of acetone (ACE), purified water (H2O), isopropanol (i-PrOH), ethanol (EtOH), and methanol (MeOH).
[0044] Furthermore, the first post-treatment in step a is specifically as follows: cooling the obtained reaction system I to room temperature, adding a mixed solution consisting of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water in the mixed solution is 1:1, and then separating the liquids, drying the organic phase and concentrating to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate.
[0045] Furthermore, the second post-treatment in step b is specifically as follows: cooling the obtained reaction system II to room temperature, filtering with suction, and obtaining 4-(4-aminophenyl)-3-methyl-4-oxobutyrate.
[0046] Furthermore, the third post-treatment in step c is specifically to cool the obtained reaction system III to 0-5° C., crystallize overnight, filter, wash the obtained filter cake with purified water, and dry to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
[0047] Furthermore, the fourth post-treatment in the step d is specifically as follows: cooling the obtained reaction system IV to 0-5°C, crystallizing overnight, filtering with suction, neutralizing the obtained filter cake with 50% potassium carbonate solution, filtering with suction, washing with purified water, adding 1,4-dioxane to the filter cake to dissolve, filtering with suction, concentrating the filtrate, and drying to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
[0048] Furthermore, the fifth post-treatment in step e is specifically to adjust the pH value of the obtained reaction system VII to 6 with an acetate solution, filter and dry to obtain a crude levosimendan; the acetate is selected from one or more of sodium acetate (CH3COONa), potassium acetate (CH3COOK), and ammonium acetate (CH3COONH4);
[0049] The refining process is specifically as follows: the crude levosimendan product and the refined liquid are mixed and refined to obtain a refined system, the refined system is crystallized and filtered in sequence to obtain a filter cake, and the filter cake is washed and dried in sequence to obtain a finished levosimendan product.
[0050] The beneficial effects of the present invention are as follows: the present invention has a reasonable design, a simple preparation method, and has the following advantages:
[0051] (1) The solvent used in the present invention is green, environmentally friendly, cheap, readily available and reusable, thus reducing production costs and being suitable for industrial production; the purity of the obtained finished product levosimendan is above 99.1%;
[0052] (2) Compared with the existing disclosed synthesis methods, the present invention has the advantages of short process route, simple operation, easy availability of raw materials, high product yield, and easy treatment of three wastes. BRIEF DESCRIPTION OF THE DRAWINGS
[0053] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0054] Figure 1 It is intermediate 1 1 H-NMR spectrum;
[0055] Figure 2 It is intermediate 1 13 C-NMR spectrum;
[0056] Figure 3 is the LC-MS spectrum of intermediate 1;
[0057] Figure 4 It is intermediate 2 1 H-NMR spectrum;
[0058] Figure 5 is the LC-MS spectrum of intermediate 2;
[0059] Figure 6 It is intermediate 3 1 H-NMR spectrum;
[0060] Figure 7 is the LC-MS spectrum of intermediate 3;
[0061] Figure 8 is the chiral HPLC spectrum of intermediate 4;
[0062] Fig. 9 It's levosimendan 1 H-NMR spectrum;
[0063] Fig.10 It's from levosimendan 13 C-NMR spectrum;
[0064] Fig.11 It is the LC-MS spectrum of levosimendan. DETAILED DESCRIPTION
[0065] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.
[0066] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this description, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.
[0067] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0068] A method for synthesizing and refining levosimendan, a method for synthesizing and refining levosimendan, specifically comprising the following steps:
[0069] Step a, synthesis of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1),
[0070] N-[4-(2-bromopropionyl)phenyl]acetamide is used as a raw material, dissolved in a first solvent, and reacted with diethyl malonate in the presence of a phase transfer catalyst system. After a reaction time t1, a reaction system I is obtained. Then, the reaction system I is subjected to a first post-treatment to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1). The chemical reaction formula is as follows:
[0071]
[0072] Step b, synthesizing 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2), dissolving the diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1) obtained in step a in a second acidic solvent, and undergoing a hydrolysis and decarboxylation reaction, and obtaining a reaction system II after a reaction time t2, and then the reaction system II undergoes a second post-treatment to obtain 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2), and the chemical reaction formula is as follows:
[0073]
[0074] Step c, synthesis of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 3),
[0075] The 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2) obtained in step b is dissolved in a third solvent and reacted with hydrazine hydrate for cyclization. After reaction time t3, a reaction system III is obtained. The reaction system III is subjected to a third post-treatment to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3). The chemical reaction formula is as follows:
[0076]
[0077] Step d: chiral separation to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 4).
[0078] The 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3) obtained in step c is dissolved in a fourth solvent and reacted with L-tartaric acid. After reaction time t4, a reaction system IV is obtained. The reaction system IV is subjected to a fourth post-treatment to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 4). The chemical reaction formula is as follows:
[0079]
[0080] Step e: condensation to obtain levosimendan,
[0081] The (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 4) obtained in step d is dissolved in the fifth acidic solvent to obtain reaction system V, then cooled, and subjected to diazotization reaction with nitrite, and after reaction time t5, reaction system VI is obtained, and malononitrile solution is slowly added dropwise at low temperature, and then after reaction time t6 at room temperature, reaction system VII is obtained, and then reaction system VII is subjected to the fifth post-treatment to obtain crude levosimendan; and then the crude levosimendan is refined with a refined liquid to obtain finished levosimendan, and the chemical reaction formula is as follows:
[0082]
[0083] In step a above:
[0084] The phase transfer catalytic system consists of a phase transfer catalyst and an inorganic salt; the mass ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the first solvent is 1:(3-10); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the phase transfer catalyst is 1:(0.1-0.5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the inorganic salt is 1:(2-5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to diethyl malonate is 1:(1.1-1.5); the reaction temperature is 70-90°C, and the reaction time t1 is 8-12h;
[0085] The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide (TBAB), tetrahexylammonium bromide (THAB), and tetrabutylammonium iodide (TBAI); the inorganic salt is selected from one or more of potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), and dipotassium hydrogen phosphate (K2HPO4); the first solvent is selected from one or more of acetonitrile (CH3CN), 1,2-dichloroethane (DCE), and isopropyl alcohol (i-PrOH);
[0086] The first post-treatment is specifically as follows: cooling the obtained reaction system I to room temperature, adding a mixed solution consisting of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water in the mixed solution is 1:1, and then separating the liquids, drying the organic phase and concentrating to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate.
[0087] In the above step b, the molar ratio of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate to the second acidic solvent is 1:(20-30); the reaction temperature of the hydrolysis decarboxylation reaction is 80-100° C., and the reaction time t2 is 8-12 h;
[0088] In the above step b:
[0089] The second acidic solvent is selected from one or more of hydrogen chloride-isopropanol solution (HCl-i-PrOH), hydrochloric acid solution (HCl-H2O), and hydrogen chloride-ethanol solution (HCl-EtOH); the molar concentration of the second acidic solvent is 4 mol / L to 9 mol / L;
[0090] The second post-treatment is specifically as follows: cooling the obtained reaction system II to room temperature, filtering with suction, and obtaining 4-(4-aminophenyl)-3-methyl-4-oxobutyrate.
[0091] In step c above:
[0092] The mass ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to the third solvent is 1:(10-15); the molar ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to hydrazine hydrate is 1:(1.5-4); the cyclization reaction temperature is 80-100° C., and the reaction time t3 is 2-4 hours;
[0093] The third solvent is selected from one or more of ethanol (EtOH), purified water (H2O), and isopropanol (i-PrOH); the concentration of hydrazine hydrate is 80-85wt%;
[0094] The third post-treatment is specifically to cool the obtained reaction system III to 0-5°C, crystallize overnight, filter, wash the obtained filter cake with purified water, and dry to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
[0095] In step d above:
[0096] The mass ratio of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to the fourth solvent is 1:(40-60); the molar ratio of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to L-tartaric acid is 1:(1.5-2); the reaction temperature after dissolution is 70-80° C., and the reaction time t4 is 2-4 hours;
[0097] The fourth solvent is selected from one or more of ethanol (EtOH), dioxane (1,4-Dioxane), and isopropanol (i-PrOH);
[0098] The fourth post-treatment is specifically to cool the obtained reaction system IV to 0-5°C, crystallize overnight, filter with suction, add 50% potassium carbonate solution to neutralize the obtained filter cake, filter with suction, wash with purified water, add 1,4-dioxane to dissolve the filter cake, filter with suction, concentrate the filtrate, and dry it to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
[0099] In the above step e:
[0100] The mass ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to the fifth acidic solvent is 1:(50-60); the reaction system V is cooled to -5-5°C, and the nitrite solution is slowly added dropwise; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to nitrite is 1:(1.5-2.0), and the reaction time t5 is 1.5-3h; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to malononitrile is 1:(1.2-1.5); the reaction system VI is added dropwise at a temperature of 0-5°C, and the malononitrile solution is slowly added dropwise; the reaction time t6 is 3-5h;
[0101] The fifth acidic solvent is selected from one or more of hydrochloric acid solution (HCl-H2O), sulfuric acid solution (H2SO4-H2O), phosphoric acid solution (H3PO4-H2O); the nitrite is selected from one or more of sodium nitrite (NaNO2), potassium nitrite (KNO2), calcium nitrite (Ca(NO2)2); the refined liquid is selected from one or more of acetone (ACE), purified water (H2O), isopropanol (i-PrOH), ethanol (EtOH), methanol (MeOH);
[0102] The fifth post-treatment is specifically to adjust the pH value of the obtained reaction system VII to 6 with an acetate solution, filter and dry to obtain a crude product of levosimendan; the acetate is selected from one or more of sodium acetate (CH3COONa), potassium acetate (CH3COOK), and ammonium acetate (CH3COONH4);
[0103] The refining process is specifically as follows: the crude levosimendan product and the refined liquid are mixed and refined to obtain a refined system, the refined system is crystallized and filtered in sequence to obtain a filter cake, and the filter cake is washed and dried in sequence to obtain a finished levosimendan product.
[0104] Example 1
[0105] The synthesis of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (Intermediate 1) is as follows:
[0106] In a 500 mL reaction bottle, 27 g of N-[4-(2-bromopropionyl)phenyl]acetamide was added, followed by 52.2 g of potassium dihydrogen phosphate (K2HCPO4) and 6.5 g of tetrabutylammonium bromide (TBAB), 300 mL of acetonitrile, and finally 17.6 g of diethyl malonate. The temperature was raised to reflux, and after reflux reaction for 12 h, TLC detected that there was no raw material point. The mixture was cooled to room temperature, and a mixed solution of ethyl acetate and water was added. The mixture was stirred for 10 min, separated, the organic phase was dried over anhydrous Na2SO4, and concentrated to dryness to obtain intermediate 1 (off-white solid, 20.89 g, HPLC: 95.723%).
[0107] The chemical reaction formula for synthesizing diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1) in this embodiment is:
[0108]
[0109] Example 2
[0110] The synthesis of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (Intermediate 1) is as follows:
[0111] In a 500 mL reaction bottle, 27 g of N-[4-(2-bromopropionyl)phenyl]acetamide was added, followed by 41.4 g of potassium carbonate (K2CO3) and 6.5 g of tetrabutylammonium bromide (TBAB), 300 mL of acetonitrile, and finally 17.6 g of diethyl malonate. The temperature was raised to reflux, and after reflux reaction for 9 hours, TLC detected that there was no raw material point. The mixture was cooled to room temperature, and a mixed solution of ethyl acetate and water was added. The mixture was stirred for 10 minutes, separated, the organic phase was dried over anhydrous Na2SO4, and concentrated to dryness to obtain intermediate 1 (off-white solid, 26.89 g, HPLC: 99.723%).
[0112] The chemical reaction formula for synthesizing diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate (intermediate 1) in this embodiment is:
[0113]
[0114] like Figure 1 to Figure 3 As shown, the structure of the intermediate 1 obtained in the above example was confirmed by NMR and mass spectrometry data analysis: 1H NMR (400MHz, DMSO-d6): δ10.32(s,1H),7.97(d,J=8.5Hz,2H),7.74(d,J=8.5Hz,2H),4.18(qq,J=7.6,3.7 Hz,2H),4.11–3.92(m,3H),3.76(d,J=10.6Hz,1H),2.08(s,3H),1.20(t,J=7.1Hz,3H),1.14–0.97(m,6H); 13 C NMR (100MHz, DMSO-d6): δ199.79,169.47,168.64,168.26,144.47,130.24,129.73,118.81,61.70,54.87,24.62,16.29,14.27; LC-MS(ESI)m / z:[M+H] + Calculate for,C 18 H 24 NO6,350.2,found 350.1.
[0115] Example 3
[0116] The synthesis of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (Intermediate 2) is as follows:
[0117] In a 1000 mL reaction bottle, 35 g of intermediate 1 was added, followed by 400 mL of hydrogen chloride-isopropanol solution. The temperature was raised to 90° C., and after reacting for 4 h, the mixture was cooled to room temperature, filtered, and dried to obtain intermediate 2 (off-white solid, 18.89 g, HPLC: 96.723%).
[0118] The chemical reaction formula for synthesizing 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2) in this embodiment is:
[0119]
[0120] Example 4
[0121] The synthesis of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (Intermediate 2) is as follows:
[0122] In a 1000 mL reaction bottle, 35 g of intermediate 1 was added, followed by 400 mL of 6 mol / L HCl solution, and the temperature was raised to 90°C. After reacting for 4 h, the mixture was cooled to room temperature, filtered, and dried to obtain intermediate 2 (off-white solid, 20.13 g, HPLC: 99.723%).
[0123] The chemical reaction formula for synthesizing 4-(4-aminophenyl)-3-methyl-4-oxobutyrate (intermediate 2) in this embodiment is:
[0124]
[0125] like Figure 4 and Figure 5 As shown, the structure of the intermediate 2 obtained in the above example was confirmed by NMR and mass spectrometry data analysis: 1 H NMR (400MHz, DMSO-d6): δ7.95–7.79(m,2H),7.08(d,J=8.2Hz,2H),3.78(ddt,J=13.0,10.6,6.6Hz,1H), 2.68(dd,J=16.8,9.3Hz,1H), 2.35(dd,J=16.9,4.8Hz,1H), 1.05(d,J=7.1Hz,3H); LC-MS(ESI)m / z:[M+H] + Calculate for,C 11 H 14 N3O3, 208.1, found 208.1.
[0126] Example 5
[0127] The synthesis of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 3) is as follows:
[0128] In a 500 mL reaction bottle, 24.3 g of intermediate 2 was added, followed by 300 g of EtOH and 10 g of H2O, stirred to dissolve, and then 12.4 g of 85% hydrazine hydrate was added. The temperature was raised to 85°C, and after reacting for 3 h, the mixture was cooled to room temperature, filtered, and dried to obtain intermediate 3 (off-white solid, 15.13 g, HPLC: 99.723%).
[0129] The chemical reaction formula for synthesizing 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3) in this embodiment is:
[0130]
[0131] Example 6
[0132] The synthesis of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 3) is as follows:
[0133] In a 500 mL reaction bottle, 24.3 g of intermediate 2 was added, followed by 300 g of H2O, stirred to dissolve, and 12.4 g of 85% hydrazine hydrate was added. The reaction system was heated to 85°C, reacted for 2 h, cooled to room temperature, filtered, and dried to obtain intermediate 3 (off-white solid, 18.13 g, HPLC: 99.623%).
[0134] The chemical reaction formula for synthesizing 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 3) in this embodiment is:
[0135]
[0136] like Figure 6 and Figure 7 As shown, the structure of the intermediate 3 obtained in the above example was confirmed by NMR and mass spectrometry data analysis: 1 H NMR (400MHz, DMSO-d6): δ10.65(s,1H),7.57–7.36(m,2H),6.64–6.45(m,2H),5.48(s,2H),3.25(p,J=7.3H z,1H),2.57(dd,J=16.6,6.8Hz,1H),2.14(d,J=16.6Hz,1H),1.01(d,J=7.2Hz,3H); LC-MS(ESI)m / z:[M+H] + Calculate for,C 11 H 14 N3O, 204.1, found 204.1.
[0137] Example 7
[0138] The synthesis of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Intermediate 4) is as follows:
[0139] In a 2000mL reaction bottle, 20.3g of intermediate 3 was added, followed by 800g of isopropanol, the temperature was raised to 70°C, stirred to dissolve, L-tartaric acid (27g) was added in batches, the temperature was kept at 70°C for 3 hours, the system was cooled to 0-5°C, crystallized overnight, filtered, the filter cake was neutralized by adding 50% potassium carbonate solution, filtered, washed with purified water, 1,4-dioxane was added to the filter cake to dissolve, filtered, the filtrate was concentrated, and dried to obtain intermediate 4 (off-white solid, 6.13g, chiral HPLC purity: 99.323%). Figure 8 As shown, the above compounds were subjected to chiral HPLC determination, indicating that the chiral separation method is feasible.
[0140] The chemical reaction formula for synthesizing (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (intermediate 4) in this embodiment is:
[0141]
[0142] Example 8
[0143] The synthesis of crude levosimendan is as follows:
[0144] In a 500mL reaction bottle, 20.3g of intermediate 4 and 120g of 6mol / L hydrochloric acid solution were added, the mixture was cooled to 5°C with stirring, and an aqueous sodium nitrite solution (11.0g sodium nitrite + 60g water) was slowly added dropwise. The mixture was kept at 5°C for reaction for 1.5h. Then, an aqueous malononitrile solution (8.6g malononitrile + 60g water) was added dropwise at 5°C. After the addition was completed, the mixture was heated to room temperature (30°C), and the mixture was stirred for reaction at room temperature for 3h. The pH value was then adjusted to 6.0 with sodium acetate, filtered, and washed with water to obtain a crude levosimendan (yellow solid, 24.5g, HPLC: 98.963%).
[0145] The chemical reaction formula for the synthesis of crude levosimendan in this embodiment is:
[0146]
[0147] Example 9
[0148] The synthesis of crude levosimendan is as follows:
[0149] In a 500mL reaction bottle, 20.3g of intermediate 4 and 120g of 6mol / L sulfuric acid solution were added, the temperature was cooled to 5°C while stirring, and potassium nitrite aqueous solution (13.6g sodium nitrite + 100g water) was slowly added dropwise. The mixture was kept at 5°C for 1.5h. Then, malononitrile aqueous solution (8.6g malononitrile + 60g water) was added dropwise at 5°C. After the addition was completed, the mixture was heated to room temperature (30°C), and the mixture was stirred for 3h at room temperature. Then, the pH value was adjusted to 6.0 with sodium acetate, filtered, and washed with water to obtain crude levosimendan (yellow solid, 21.5g, HPLC: 97.263%).
[0150] The chemical reaction formula for the synthesis of crude levosimendan in this embodiment is:
[0151]
[0152] Example 10
[0153] The synthesis of levosimendan is as follows:
[0154] In a 1000 mL reaction bottle, add 28.0 g of crude levosimendan, then add 150 g of acetone and 150 g of isopropanol, raise the temperature to 80°C, stir and react for 1 hour, naturally cool to room temperature (30°C), filter, wash with water, and dry to obtain levosimendan (yellow solid, 26.5 g, HPLC: 99.663%).
[0155] The chemical reaction formula for synthesizing levosimendan in this embodiment is:
[0156]
[0157] Embodiment 11
[0158] The synthesis of levosimendan is as follows:
[0159] In a 1000 mL reaction bottle, add 28.0 g of crude levosimendan, then add 150 g of acetone and 150 g of water, raise the temperature to 80°C, stir and react for 1 hour, naturally cool to room temperature (30°C), filter, wash with water, and dry to obtain levosimendan (yellow solid, 22.5 g, HPLC: 99.263%).
[0160] The chemical reaction formula for synthesizing levosimendan in this embodiment is:
[0161]
[0162] like Figures 9 to 11 As shown, the structure of levosimendan obtained in the above example was confirmed by NMR and mass spectrometry data analysis: 1 H NMR (400MHz, DMSO-d6): δ13.07(s,1H),10.98(s,1H),7.80(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H), 3.35(q,J=7.2Hz,1H),2.66(dd,J=16.8,6.9Hz,1H),2.22(d,J=16.7Hz,1H),1.05(d,J=7.3Hz,3H); 13 C NMR (100MHz, DMSO-d6): δ166.78,152.12,142.40,132.45,127.39,116.93,114.70,110.31,85.74,33.92,27.43,16.34; LC-MS(ESI)m / z:[M+H] + calcdfor,C 14 H 13 N6O, 281.1, found 281.1. This further proves that the synthesized compound is levosimendan.
[0163] In summary, the present invention has a reasonable design, a simple preparation method and the following advantages:
[0164] (1) The solvent used in the present invention is green, environmentally friendly, cheap, readily available and reusable, thus reducing production costs and being suitable for industrial production; the purity of the obtained finished product levosimendan is above 99.1%;
[0165] (2) Compared with the existing disclosed synthesis methods, the present invention has the advantages of short process route, simple operation, easy availability of raw materials, high product yield, and easy treatment of three wastes.
[0166] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for synthesizing and refining levosimendan, characterized in that: The specific steps include: Step a, synthesizing intermediate 1, intermediate 1 is diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate, N-[4-(2-bromopropionyl)phenyl]acetamide is used as a raw material, dissolved in a first solvent, and reacted with diethyl malonate in the presence of a phase transfer catalyst system. After a reaction time t1, a reaction system I is obtained. Then, the reaction system I is subjected to a first post-treatment to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate. The chemical reaction formula is as follows: Step b, synthesizing intermediate 2, intermediate 2 is 4-(4-aminophenyl)-3-methyl-4-oxobutyrate, The diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate prepared in step a is dissolved in a second acidic solvent and subjected to a hydrolysis and decarboxylation reaction. After a reaction time t2, a reaction system II is obtained. Then, the reaction system II is subjected to a second post-treatment to obtain 4-(4-aminophenyl)-3-methyl-4-oxobutyrate. The chemical reaction formula is as follows: Step c, synthesizing intermediate 3, intermediate 3 is 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, The 4-(4-aminophenyl)-3-methyl-4-oxobutyrate prepared in step b is dissolved in a third solvent and reacted with hydrazine hydrate for cyclization. After reaction time t3, a reaction system III is prepared. The reaction system III is subjected to a third post-treatment to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. The chemical reaction formula is as follows: Step d: chiral separation to obtain intermediate 4, intermediate 4 is (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, The 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone prepared in step c is dissolved in a fourth solvent and reacted with L-tartaric acid. After reaction time t4, a reaction system IV is prepared. The reaction system IV is subjected to a fourth post-treatment to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. The chemical reaction formula is as follows: Step e, condensation to obtain levosimendan, The (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone prepared in step d is dissolved in the fifth acidic solvent to prepare reaction system V, then cooled, and subjected to diazotization reaction with nitrite, after reaction time t5, to prepare reaction system VI, and the malononitrile solution is slowly added dropwise at low temperature, and then after reaction time t6 at room temperature, to prepare reaction system VII, and then reaction system VII is subjected to the fifth post-treatment to obtain crude levosimendan; then the crude levosimendan is refined with a refined liquid to obtain finished levosimendan, and the chemical reaction formula is as follows:
2. A method for synthesizing and refining levosimendan according to claim 1, characterized in that: In the step a, the phase transfer catalytic system consists of a phase transfer catalyst and an inorganic salt; The mass ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the first solvent is 1:(3-10); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the phase transfer catalyst is 1:(0.1-0.5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to the inorganic salt is 1:(2-5); the molar ratio of N-[4-(2-bromopropionyl)phenyl]acetamide to diethyl malonate is 1:(1.1-1.5); the reaction temperature is 70-90°C, and the reaction time t1 is 8-12h; The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrahexylammonium bromide, and tetrabutylammonium iodide; the inorganic salt is selected from one or more of potassium carbonate, cesium carbonate, and dipotassium hydrogen phosphate; and the first solvent is selected from one or more of acetonitrile, 1,2-dichloroethane, and isopropanol.
3. A method for synthesizing and refining levosimendan according to claim 1, characterized in that: In the step b, the molar ratio of diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate to the second acidic solvent is 1:(20-30); the reaction temperature of the hydrolysis decarboxylation reaction is 80-100° C., and the reaction time t2 is 8-12 h; In the step b, the second acidic solvent is selected from one or more of hydrogen chloride-isopropanol solution, hydrochloric acid solution, and hydrogen chloride-ethanol solution; and the molar concentration of the second acidic solvent is 4 mol / L to 9 mol / L.
4. A method for synthesizing and refining levosimendan according to claim 1, characterized in that: In the step c, the mass ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to the third solvent is 1:(10-15); the molar ratio of 4-(4-aminophenyl)-3-methyl-4-oxobutyrate to hydrazine hydrate is 1:(1.5-4); the cyclization reaction temperature is 80-100° C., and the reaction time t3 is 2-4 hours; In the step c, the third solvent is selected from one or more of ethanol, purified water, and isopropanol; and the concentration of hydrazine hydrate is 80-85 wt%.
5. A method for synthesizing and refining levosimendan according to claim 1, characterized in that: In the step e, the mass ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to the fifth acidic solvent is 1:(50-60); In the step e, the reaction system V is cooled to -5 to 5°C, and a nitrite solution is slowly added dropwise; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to nitrite is 1:(1.5 to 2.0), and the reaction time t5 is 1.5 to 3h; the molar ratio of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to malononitrile is 1:(1.2 to 1.5); In the step e, the temperature of adding the reaction system VI is 0-5°C, and the malononitrile solution is slowly added dropwise; the reaction time t6 is 3-5h; In the step e, the fifth acidic solvent is selected from one or more of hydrochloric acid solution, sulfuric acid solution, and phosphoric acid solution; the nitrite is selected from one or more of sodium nitrite, potassium nitrite, and calcium nitrite; and the refined liquid is selected from one or more of acetone, purified water, isopropanol, ethanol, and methanol.
6. The method for synthesizing and refining levosimendan according to claim 1, characterized in that: The first post-treatment in step a is specifically as follows: cooling the obtained reaction system I to room temperature, adding a mixed solution consisting of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water in the mixed solution is 1:1, and then separating the liquids, drying the organic phase and concentrating to obtain diethyl 2-(1-(4-acetylaminophenyl)-1-oxopropane-2-yl)malonate.
7. The method for synthesizing and refining levosimendan according to claim 1, characterized in that: The second post-treatment in step b is specifically as follows: cooling the obtained reaction system II to room temperature, filtering with suction, and obtaining 4-(4-aminophenyl)-3-methyl-4-oxobutyrate.
8. The method for synthesizing and refining levosimendan according to claim 1, characterized in that: The third post-treatment in step c is specifically to cool the obtained reaction system III to 0-5° C., crystallize overnight, filter, wash the obtained filter cake with purified water, and dry to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
9. The method for synthesizing and refining levosimendan according to claim 1, characterized in that: The fourth post-treatment in step d is specifically as follows: cooling the obtained reaction system IV to 0-5° C., crystallizing overnight, filtering with suction, neutralizing the obtained filter cake with 50% potassium carbonate solution, filtering with suction, washing with purified water, adding 1,4-dioxane to the filter cake to dissolve, filtering with suction, concentrating the filtrate, and drying to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
10. The method for synthesizing and refining levosimendan according to claim 1, characterized in that: The fifth post-treatment in step e is specifically to adjust the pH value of the obtained reaction system VII to 6 with an acetate solution, filter and dry to obtain a crude levosimendan product; the acetate is selected from one or more of sodium acetate, potassium acetate and ammonium acetate; The refining process is specifically as follows: the crude levosimendan product and the refined liquid are mixed and refined to obtain a refined system, the refined system is crystallized and filtered in sequence to obtain a filter cake, and the filter cake is washed and dried in sequence to obtain a finished levosimendan product.