CN111377858A - Preparation method of milrinone - Google Patents
Preparation method of milrinone Download PDFInfo
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- CN111377858A CN111377858A CN201811644143.0A CN201811644143A CN111377858A CN 111377858 A CN111377858 A CN 111377858A CN 201811644143 A CN201811644143 A CN 201811644143A CN 111377858 A CN111377858 A CN 111377858A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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Abstract
The invention discloses a preparation method of milrinone, belonging to the technical field of drug synthesis. The method takes 1- (4-pyridyl) -2-acetone as a raw material to react with 2-cyano-3-ethoxy acrylamide under the alkaline condition by heating, so as to obtain the milrinone. The method for preparing milrinone has the advantages of simple and convenient operation, high safety and high yield, and is suitable for industrial large-scale production. The obtained high-purity milrinone finished product has the appearance and the purity reaching the standard.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of milrinone.
Background
Milrinone (Milrinone), also known as metyrapone, has the CAS number: 78415-72-2, is the common name of 1, 6-dihydro-2-methyl-6-oxo- [3,4' -bipyridine ] -5-carbonitrile, was first developed and developed by Sterling corporation in the United states, was first approved by the FDA in the United states in 1987, was officially marketed in the United states in 1992, was subsequently marketed in countries such as the United kingdom, France, Germany, the Netherlands, Belgium and Brazil, and was clinically used as a lactate salt, mainly for the treatment of refractory heart failure and heart failure patients who have undergone digitalis intoxication, and recent studies showed that Milrinone can also be used for low-cardiac-ejection syndrome after cardiac surgery extracorporeal circulation, relief of bypass vasospasm, improvement of heart function and anti-inflammatory response in heart orthotopic transplantation patients, improvement of visceral blood flow perfusion, and the like. The chemical structure is as follows:
milrinone is a non-digitalis and non-catecholamine heart-strengthening drug, is a phosphodiesterase inhibitor representative drug, is a homologous drug of Amrinone, can selectively inhibit phosphodiesterase III (PDE III) in cardiac muscle cells, changes the transport of calcium ions inside and outside the cells, enhances myocardial contractility, and plays an increasingly important role in the aspects of treating Congestive Heart Failure (CHF), dilating blood vessels and the like. The efficacy of the compound is 10-30 times stronger than that of amrinone, and adverse reactions such as thrombocytopenia and hypotension of the amrinone are avoided.
The currently reported synthesis processes of milrinone mainly include the following methods:
the first method is to use a "straight line" synthetic route (e.g. US4469871A, US4413127A, EP0095152, US4313951A, J.Med. chem.,1986,29,635-640, CN103288725B, CN104387320B, CN1253439C, CN106243032A, CN105777626A, CN104526975A, CN101143844A, etc.) to prepare 1- (4-pyridyl) -2-propanone by using 4-methylpyridine as a starting material, wherein the reaction can be realized by two routes, the first route is to react with ethyl acetate under the condition of N-butyl lithium or phenyl lithium, the second route is to react 4-methylpyridine and acetyl chloride for 16h at room temperature, then 1- (4-pyridyl) -2-propanone reacts with trialkyl orthoformate or N, N-dimethylformamide dimethyl acetal (DMF-DMA) and then reacts with α -cyanoacetamide or malononitrile by a "one pot" boiling "reaction to obtain a crude milrinone-one-micron-one-acetonide product, and then the injection-grade milrinone-one-micron-one-acetonide product is synthesized by recrystallization, the straight line synthetic route has a lower toxicity and a higher yield than the linear synthetic route using 4-pyridyl-malononitrile, thereby resulting in the final cyclization step.
The second method is a "convergent" synthetic route (e.g. Heterocycles, Vol.23, NO.6,1985,1479-1482, CN103664773A, etc.) which also uses 4-methylpyridine as the starting material to prepare 1- (4-pyridyl) -2-acetone, then uses malononitrile and triethyl orthoformate as the starting materials to prepare α -ethoxymethylenemalononitrile, and finally reacts 1- (4-pyridyl) -2-acetone and α -ethoxymethylenemalononitrile to prepare crude milrinone, and the crude milrinone is obtained by recrystallization to obtain refined milrinone, the crude color obtained by the method is red, and the final product is obtained by three refining processes, the total yield is only about 38%, and the yield is not obviously superior to the yield of 70% of other routes.
In addition, the document adv.Synth.Catal.,2010,352, 3255-A3266 discloses the basis that the synthesis of milrinone by one-step direct coupling reaction has poor reaction performance, and the author uses benzyl to protect hydroxyl and then couples, and finally performs hydrogenolysis and debenzylation to prepare a milrinone finished product, so that the reaction steps are prolonged and are not suitable for industrial amplification production.
The fourth method is that the document Heterocycles, Vol.31, NO.3,1990,523-527 discloses a method which takes 2-alkoxy-5-bromo-6-methylpyridine as a raw material, under the alkaline condition of n-butyl lithium, the raw material is catalyzed by cuprous iodide to react with carbethoxypyridine hydrochloride at the temperature of-78 ℃, then the reaction product is oxidized by air to prepare a 3,4 '-bipyridine derivative, the 3,4' -bipyridine derivative is subjected to hydrogenolysis deprotection and NBS bromination, and finally the product is reacted with potassium cyanide to prepare the target product. The synthetic route is complex, ethoxycarbonyl pyridine hydrochloride needs to be prepared in advance, the reaction condition is harsh, the reaction needs to be carried out at-78 ℃, the requirement on equipment is high, and the introduction of the cyano adopts potassium cyanide which is a highly toxic substance, so that the process safety is low, and the method is not suitable for industrial production.
In summary, in the preparation method for milrinone that has been reported, there are mainly the following problems:
(1) the milrinone prepared by the existing milrinone synthesis method has low purity and red color, and the predetermined effect is difficult to achieve by further refining.
(2) The synthesis process of milrinone generally has the problems of longer reaction steps and lower overall yield.
(3) The existing milrinone synthesis route is complex, the reaction conditions are harsh, and some virulent potassium cyanide or malononitrile needs to be applied, so that the process has low operation safety and difficult realization of industrial production.
Summarizing more problems in the prior art, the research and search for a preparation method of milrinone which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrial production still needs to solve the problems at present.
Disclosure of Invention
Aiming at the problems of the existing milrinone preparation technology, the invention provides a novel preparation method of milrinone. The method has the advantages of mild reaction conditions, simple and convenient operation process and low production cost, and the prepared milrinone product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of milrinone takes 1- (4-pyridyl) -2-acetone, namely SM-1, as a raw material to react with 2-cyano-3-ethoxy acrylamide, namely SM-2, so as to obtain the milrinone, and the reaction formula is as follows:
a preparation method of milrinone specifically comprises the following steps:
adding 1- (4-pyridyl) -2-acetone and 2-cyano-3-ethoxy acrylamide into an organic solvent, uniformly stirring, reacting at a controlled temperature in an alkaline environment, completely reacting by TLC (thin layer chromatography), and cooling the reaction solution to room temperature after the reaction is finished; and adding acid into the reaction liquid to adjust the pH value, stirring and crystallizing until all the similar white solids are separated out, filtering and drying to obtain the milrinone.
Preferably, the feeding molar ratio of SM-1 to SM-2 is 1: 1.2 to 2.0, wherein 1: 1.6.
preferably, the organic solvent is one of methanol, ethanol, isopropanol, tert-butanol or a combination thereof, wherein ethanol is particularly preferred.
Preferably, the mass-to-volume ratio of the SM-1 to the organic solvent is 1: 5-10 g/mL.
Preferably, the alkali for adjusting the alkaline environment of the solution is an inorganic alkali or an organic alkali, the inorganic alkali is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic alkali is an alkali or an aqueous solution thereof; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide; among them, an aqueous sodium hydroxide solution is particularly preferable.
Preferably, the pH value of the alkaline environment is 12-14.
Preferably, the reaction temperature is 60-85 ℃, and the specific reaction temperature is the reflux temperature of the selected organic solvent.
Preferably, the acid is one of formic acid, acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or a combination thereof, wherein acetic acid is particularly preferred.
Preferably, the pH value is adjusted to 6-7 by adding acid.
The invention provides a new preparation method of convergent milrinone, which is simple and convenient to operate, effectively avoids the use of potassium cyanide or malononitrile highly toxic products, and improves the operation safety; the appearance and the purity of the white crystalline milrinone product synthesized by the method reach the standard; the reaction yield of the milrinone synthesized by the method is improved from about 70 percent to about 90 percent, the utilization rate and the reaction yield of raw materials are greatly improved, the production cost is saved, and the method is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
Materials used in the experiment: the compound 1- (4-pyridyl) -2-propanone (SM-1) is commercially available or may be prepared by reference to the prior art disclosures; the compound 2-cyano-3-ethoxyacrylamide (SM-2) is commercially available or can be prepared by reference to the prior art; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure. .
The invention adopts HPLC to measure the purity of milrinone, and the chromatographic conditions are as follows:
a chromatographic column: agilent ZORBAX Rx-C8(4.6mm×250mm,5.0μm)；
Mobile phase: dipotassium phosphate buffer (2.7g K)2HPO4+2.4mL triethylamine +800mL water with H3PO4pH was adjusted to 7.5) -acetonitrile (80: 20) (ii) a
Column temperature: 30 ℃;
detection wavelength: 220 nm;
flow rate: 1.0 mL/min;
sample introduction amount: 20 μ L.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.57g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.42g, 0.16mol) into ethanol (100mL), uniformly stirring, dropwise adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13, controlling the temperature to be 75-80 ℃ for reaction, after the TLC detection reaction is completed, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 19.07g of white crystal milrinone, wherein HPLC: 99.98% and yield 90.4%.
Example 2
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.54g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 16.82g, 0.12mol) into methanol (80mL), uniformly stirring, and dropwise adding 7.0mol/L potassium hydroxide solution to adjust the pH value to 12; controlling the temperature to be 65-70 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 18.63g of white crystal milrinone, and performing HPLC: 99.94% and 88.3% yield.
Example 3
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.52g, 0.10mol) and 2-cyano-3-ethoxyacrylamide SM-2(15.42g, 0.11mol) into ethanol (100mL), uniformly stirring, and dropwise adding 8.0mol/L barium hydroxide solution to adjust the pH value to 13; controlling the temperature to be 75-80 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; regulating the pH value of the reaction solution to 6-7 by using formic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 17.68g of white crystal milrinone, and performing HPLC: 99.84% and yield 83.8%.
Example 4
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.55g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 28.03g, 0.20mol) into ethanol (120mL), uniformly stirring, and dropwise adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 14; controlling the temperature to be 75-80 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; and (3) regulating the pH value of the reaction solution to 6-7 by using hydrochloric acid, stirring and crystallizing, leaching when all the similar white solids are separated out, and drying a filter cake in vacuum to obtain 18.93g of white crystal milrinone, wherein HPLC: 99.92% and a yield of 89.7%. .
Example 5
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.57g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 29.43g, 0.21mol) into ethanol (100mL), uniformly stirring, and dropwise adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13; controlling the temperature to be 75-80 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 18.42g of white crystal milrinone, and performing HPLC: 99.72%, yield 87.3%.
Example 6
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.54g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.42g, 0.16mol) into ethanol (100mL), uniformly stirring, dropwise adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 11.5, controlling the temperature to be 75-80 ℃ for reaction, after the TLC detection reaction is completed, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 16.96g of white crystal milrinone, and performing HPLC: 98.75% and a yield of 80.4%.
Example 7
Adding 1- (4-pyridyl) -2-acetone (SM-1, 13.56g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.44g, 0.16mol) into ethanol (100mL), uniformly stirring, dropwise adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13, controlling the temperature to be 75-80 ℃ for reaction, after the TLC detection reaction is completed, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 5.0-5.5 by using acetic acid, stirring and crystallizing, leaching after all the off-white solids are separated out, drying a filter cake in vacuum to obtain 17.15g of white crystal milrinone, and performing HPLC: 99.75% and a yield of 81.3%.
Example 8
Adding sodium ethoxide into ethanol (80mL) while stirring, and adjusting the pH value of the solution to 13; adding 1- (4-pyridyl) -2-acetone (SM-1, 13.53g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.45g, 0.16mol) into the ethanol solution, stirring uniformly while supplementing sodium ethoxide to adjust the pH value of the solution to 13; controlling the temperature to be 75-80 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; regulating the pH value of the reaction solution to 6-7 by using hydrochloric acid, stirring and crystallizing, performing suction filtration when all the similar white solids are separated out, and performing vacuum drying on a filter cake to obtain 19.01g of white crystal milrinone, and performing HPLC: 99.95% and yield 90.1%.
Example 9
Adding sodium methoxide into methanol (70mL) while stirring, and adjusting the pH value of the solution to 12; adding 1- (4-pyridyl) -2-acetone (SM-1, 13.54g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.43g, 0.16mol) into the methanol solution, and then adding sodium methoxide to adjust the pH value of the solution to 12 while stirring and mixing uniformly; controlling the temperature to be 65-70 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; regulating the pH value of the reaction liquid to 6-7 by using hydrobromic acid, stirring and crystallizing, leaching when all similar white solids are separated out, and drying a filter cake in vacuum to obtain 18.95g of white crystal milrinone, HPLC: 99.93%, yield 89.8%.
Example 10
Adding sodium isopropoxide into isopropanol (80mL) while stirring, and adjusting the pH value of the solution to 13; adding 1- (4-pyridyl) -2-acetone (SM-1, 13.52g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.44g, 0.16mol) into the isopropanol solution, stirring and uniformly mixing, and supplementing sodium isopropoxide while adjusting the pH value of the solution to 13; controlling the temperature to be 80-85 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction liquid to 6-7 with hydroiodic acid, stirring for crystallization, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 18.82g of white crystal milrinone, and performing HPLC: 99.90% and 89.2% yield.
Example 11
Adding sodium tert-butoxide into tert-butanol (80mL) while stirring, and adjusting the pH value of the solution to 12; adding 1- (4-pyridyl) -2-acetone (SM-1, 13.50g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.41g, 0.16mol) into the tert-butyl alcohol solution, stirring and mixing uniformly, and supplementing sodium tert-butoxide to adjust the pH value of the solution to 12; controlling the temperature to be 80-85 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 18.65g of white crystal milrinone, and performing HPLC: 99.91% and 88.4% yield.
Example 12
Adding sodium hydroxide into ethanol (100mL) while stirring, and adjusting the pH value of the solution to 14; adding 1- (4-pyridyl) -2-acetone (SM-1, 13.52g, 0.10mol) and 2-cyano-3-ethoxyacrylamide (SM-2, 22.46g, 0.16mol) into the ethanol solution, and adding sodium hydroxide while stirring uniformly to adjust the pH value of the solution to 14; controlling the temperature to be 75-80 ℃ for reaction, detecting by TLC (thin layer chromatography) that the reaction is complete, finishing the reaction, and cooling the reaction solution to room temperature; adjusting the pH value of the reaction solution to 6-7 by using acetic acid, stirring and crystallizing, leaching when all the off-white solids are separated out, and drying a filter cake in vacuum to obtain 19.03g of white crystal milrinone, and performing HPLC: 99.96% and yield 90.2%.
Claims (10)
1. The preparation method of milrinone is characterized in that 1- (4-pyridyl) -2-acetone, namely SM-1, is used as a raw material to react with 2-cyano-3-ethoxy acrylamide, namely SM-2, so as to obtain the milrinone, and the reaction formula is as follows:
2. the method for the preparation of milrinone according to claim 1, characterized in that it comprises the following steps:
adding 1- (4-pyridyl) -2-acetone and 2-cyano-3-ethoxy acrylamide into an organic solvent, uniformly stirring, controlling the temperature to be controlled to be over under an alkaline environment, cooling the reaction liquid to room temperature, crystallizing, filtering and drying to obtain the milrinone.
3. The process for the preparation of milrinone according to claim 2, wherein the molar ratio of SM-1 to SM-2 fed is 1: 1.2 to 2.0.
4. The method for preparing milrinone according to claim 2, wherein the organic solvent is one or a combination of methanol, ethanol, isopropanol and tert-butanol.
5. The method for preparing milrinone according to claim 2, wherein the alkali of the conditioning solution in an alkaline environment is an inorganic alkali or an organic alkali, and the inorganic alkali is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide.
6. The method for preparing milrinone according to claim 2, wherein the alkaline environment has a pH of 12 to 14.
7. The method for preparing milrinone according to claim 2, wherein the reaction temperature is 60-85 ℃.
8. The method according to claim 2, wherein the crystallization is performed by adding an acid to the reaction solution to adjust the pH value and stirring the solution to crystallize the milrinone.
9. The method of claim 8, wherein the acid is one of formic acid, acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, or a combination thereof.
10. The method for preparing milrinone according to claim 8, wherein the pH is adjusted to 6 to 7 by adding an acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220029527A (en) * | 2020-08-31 | 2022-03-08 | 이화여자대학교 산학협력단 | Method of preraring amrinone derivatives including regioselective suzuki coupling reaction |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20220029527A (en) * | 2020-08-31 | 2022-03-08 | 이화여자대학교 산학협력단 | Method of preraring amrinone derivatives including regioselective suzuki coupling reaction |
| KR102659144B1 (en) | 2020-08-31 | 2024-04-22 | 이화여자대학교 산학협력단 | Method of preraring amrinone derivatives including regioselective suzuki coupling reaction |
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