CN111718295B - Preparation method of high-purity milrinone - Google Patents
Preparation method of high-purity milrinone Download PDFInfo
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Abstract
The invention provides a preparation method of milrinone, and belongs to the technical field of drug synthesis. At room temperature, the milrinone intermediate compound I and alpha-cyanoacetamide are added into an organic solvent, stirred uniformly, reacted in an alkaline environment at a controlled temperature, and after the reaction is finished, the reaction solution is cooled to room temperature, and is subjected to crystallization, filtration and drying to obtain milrinone. The method for preparing the milrinone agricultural product is simple and convenient to operate, high in safety and high in yield, is suitable for industrial scale-up production, and the obtained high-purity milrinone finished product has the appearance and purity reaching the standards.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of high-purity milrinone.
Background
Milrinone (Milrinone), also known as fenpropathrin, has CAS number: 78415-72-2, which is a common name of 1, 6-dihydro-2-methyl-6-oxo- [3,4' -bipyridine ] -5-carbonitrile, was first developed and successfully developed by Sterling corporation in the United states, was approved by the FDA for the first time in 1987, was formally marketed in the United states in 1992, and was subsequently marketed in the United kingdom, france, germany, netherlands, belgium, brazil and other countries, and was clinically used as its lactate, and was mainly suitable for treating refractory heart failure and heart failure patients who have developed digitalis poisoning, recent studies showed that Mirinone can also be used for treating hypocenter discharge syndrome after cardiac surgical extracorporeal circulation, relieving bypass vasospasm, improving heart function and anti-inflammatory response in heart in situ transplant patients, improving visceral blood perfusion and the like. The chemical structure is as follows:
the milrinone series non-digitalis and non-catecholamines cardiotonic is a representative drug of phosphodiesterase inhibitors, is a homologous drug of Amrinone (Amrinone), can selectively inhibit phosphodiesterase III (PDE III) in myocardial cells, change the transportation of calcium ions inside and outside cells, strengthen the contractility of the myocardial cells, and plays an increasingly important role in treating Congestive Heart Failure (CHF), dilating blood vessels and the like. The efficacy is 10-30 times stronger than that of amrinone, and adverse reactions such as thrombocytopenia and hypotension of the latter are avoided.
The currently reported synthesis processes of milrinone mainly comprise the following methods:
the first type of approach is to use a "straight line" synthetic route (e.g., US4469871a, US4413127a, EP0095152, US4313951a, j. Med. Chem.) 1986,29,635-640, cn103288725b, cn 104387330 b, cn1253439c, cn106243032A, cn105777626a, cn104526975A, cn101143844a, etc.): firstly, 4-methylpyridine is used as a starting material to prepare 1- (4-pyridyl) -2-acetone, and the reaction can be realized through two paths, wherein the first path is to react with ethyl acetate under the condition of n-butyl lithium or phenyl lithium. The second route is that 4-methylpyridine and acetyl chloride are reacted at room temperature for 16h. Then 1- (4-pyridyl) -2-acetone reacts with trialkyl orthoformate or N, N-dimethylformamide dimethyl acetal (DMF-DMA) and then reacts with alpha-cyanoacetamide or malononitrile to obtain crude milrinone by one-pot reaction, and then injection-grade fine milrinone is obtained by recrystallization. The linear synthetic route is longer, the utilization rate of 1- (4-pyridyl) -2-acetone is lower, and the yield is lower, so that the production cost is higher; in the final cyclization step, the malononitrile employed is more toxic.
The second type of approach is to use "convergent" synthetic routes (e.g., heteromyces, vol.23, no.6,1985,1479-1482, NC 103664773A, etc.): the method also uses 4-methylpyridine as a starting material to prepare 1- (4-pyridyl) -2-acetone, then uses malononitrile and triethyl orthoformate as raw materials to prepare alpha-ethoxymethylenemalononitrile, finally reacts the 1- (4-pyridyl) -2-acetone and the alpha-ethoxymethylenemalononitrile to prepare a milrinone crude product, and recrystallizes to obtain the fine milrinone. The crude product obtained by the method has reddening color, needs three times of refining to obtain a final product, has the total yield of about 38 percent, and has no obvious advantage compared with the yield of 70 percent of other routes.
The third method is that acetone and ethyl formate are used as starting materials, condensed under alkaline condition, cyclized with alpha-cyanoacetamide, and then brominated by NBS to prepare a key intermediate, and finally subjected to Suzuki coupling reaction with 1-pyridine boric acid to synthesize milrinone. The process is applied to dichloroethane with high toxicity in bromination reaction as a reaction solvent. In addition, the literature adv.synth.Catal, 2010,352,3255-3266 discloses that the scheme synthesizes the basis of poor reaction performance of milrinone through one-step direct coupling reaction, the authors protect hydroxyl by benzyl and then couple the hydroxyl, and finally hydrogenate and debenzylate the hydroxyl to prepare the milrinone finished product, so that the reaction steps are prolonged, and the method is also not suitable for industrial scale-up production.
A fourth method is that 2-alkoxy-5-bromo-6-methylpyridine is used as a raw material, the raw material is reacted with ethoxyformylpyridine hydrochloride at-78 ℃ under the alkaline condition of n-butyllithium by cuprous iodide catalysis, 3,4 '-bipyridine derivatives are prepared by air oxidation, the 3,4' -bipyridine derivatives are subjected to hydrogenolysis to remove protective groups, NBS is brominated, and finally the target products are prepared by reaction with potassium cyanide. The synthetic route is complex, the ethoxyformyl pyridine hydrochloride needs to be prepared in advance, the reaction condition is harsh, the equipment requirement is high at the temperature of minus 78 ℃, and meanwhile, the cyano group is introduced by adopting the virulent potassium cyanide, so that the process safety is low, and the method is not suitable for industrial production.
In summary, in the reported preparation methods of milrinone, the following problems mainly exist:
(1) The milrinone prepared by the existing milrinone synthesis method has low purity and reddish color, and the predetermined effect is difficult to achieve by further refining means.
(2) In the synthesis process of milrinone, the reaction steps are generally longer, so that the overall yield is lower.
(3) The existing milrinone has a complex synthetic route and harsh reaction conditions, and needs to use some highly toxic potassium cyanide or malononitrile, so that the process operation safety is reduced, and the industrial production is difficult to realize.
Summarizing more problems in the prior art, research and search for a preparation method which is mild in reaction condition, simple and convenient in operation process, high in product yield and purity and low in production cost and is suitable for industrial production of milrinone still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing milrinone preparation technology, the invention provides a novel milrinone preparation method. The method has the advantages of mild reaction conditions, simple operation process and low production cost, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of milrinone, which is characterized in that a milrinone intermediate compound I reacts with alpha-cyano acetamide to obtain milrinone, and the synthetic route is as follows:
the preparation method of milrinone specifically comprises the following steps:
at room temperature, the milrinone intermediate compound I and alpha-cyanoacetamide are added into an organic solvent, stirred uniformly, reacted in an alkaline environment at a controlled temperature, and after the reaction is finished, the reaction solution is cooled to room temperature, and is subjected to crystallization, filtration and drying to obtain milrinone.
Preferably, the molar ratio of the milrinone intermediate compound I to the alpha-cyanoacetamide is 1:1.1 to 1.7, of which 1 is particularly preferred: 1.4.
preferably, the organic solvent is one or a combination of methanol, ethanol, isopropanol and tert-butanol, wherein ethanol is particularly preferred.
Preferably, the alkali for regulating the alkaline environment of the solution is inorganic alkali or organic alkali, and the inorganic alkali is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, wherein the inorganic alkali is alkali or aqueous solution thereof; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide; among them, aqueous sodium hydroxide solution is particularly preferable.
Preferably, the pH value of the alkaline environment is 12-14.
Preferably, the temperature-controlled reaction is a temperature-controlled reflux reaction.
In a preferred scheme, the crystallization method is to add acid to the reaction liquid to adjust the pH value, stir and crystallize; preferably, the acid is one or a combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, with acetic acid being particularly preferred; preferably, the pH value is adjusted to 6-7 by adding acid.
The preparation method of the milrinone intermediate compound I comprises the following steps: under the protection of inert gas, under the condition of room temperature, adding a catalyst into a reaction solvent, stirring and uniformly mixing, adding an aqueous solution of alkali, a compound SM-1 and a compound SM-2 into the reaction solvent, stirring and controlling the temperature to react, finishing the reaction, filtering, adding filtrate into purified water, extracting an extractant, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a milrinone intermediate compound I, wherein the synthetic route is as follows:
wherein X is one of I, tfO and Br; r is OH, CH 2 CH 3 One of them.
Preferably, X is Br and R is OH.
Preferably, the catalyst is Pd (PPh 3 ) 4 [ tetrakis (triphenylphosphine) palladium]、Pd(PPh 3 ) 2 Cl 2 [ Ditriphenylphosphine palladium dichloride ]]、Pd(dppf)Cl 2 [ [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride]、Pd 2 (dba) 3 [ tris (dibenzylidene) propylKetone) dipalladium]、Pd(OAc) 2 (PPh 3 ) 2 [ Palladium bis (triphenylphosphine) diacetate]One or a combination thereof, particularly preferably Pd (PPh 3 ) 4 。
Preferably, the reaction solvent is one or a combination of ethanol, isopropanol, acetonitrile, 1, 4-dioxane, water, toluene, N-dimethylformamide and dimethyl sulfoxide, wherein dimethyl sulfoxide is particularly preferred.
Preferably, the base is K 2 CO 3 、Na 2 CO 3 、Cs 2 CO 3 、K 3 PO 4 、Na 3 PO 4 One of NaOAc, KOAc or a combination thereof, of which KOAc is particularly preferred.
Preferably, the feeding mole ratio of the compound SM-1 to the compound SM-2 to the base to the catalyst is 1:1.05 to 1.30:2.6 to 4.5:0.03 to 0.07, of which 1:1.2:3.4:0.05.
preferably, the mass-volume ratio of the compound SM-1 to the reaction solvent is 1:10-15 g/mL.
Preferably, the molar concentration of the aqueous alkali solution is 6.0-7.0 mol/L.
Preferably, the temperature-controlled reaction is a temperature-controlled reflux reaction.
Preferably, the volume of the purified water is 3 to 5 times of the volume of the reaction solvent.
Preferably, the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tertiary butyl ether, wherein ethyl acetate is particularly preferred.
In the present invention, the inert gas is usually nitrogen or argon, and among them, argon is particularly preferable.
The invention has the beneficial effects that:
the invention provides a preparation method of high-purity milrinone, which is simple and convenient in route operation, effectively avoids the use of potassium cyanide or malononitrile highly toxic substances, and improves the operation safety; the appearance and purity of the white crystal milrinone synthesized by the invention all reach the standards; under the preferential condition, the milrinone synthesized by the route has the general yield of about 70 percent which is improved to more than 90 percent, greatly improves the utilization rate of raw materials, saves the production cost and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: the compound α -substituted acetoacetal (SM-1) is commercially available or can be prepared by reference to the techniques disclosed herein; the materials used in the other experiments were not of the indicated source and specification, either commercially available analytically pure or chemically pure.
The invention adopts HPLC to measure the purity of milrinone, and the chromatographic conditions are as follows:
chromatographic column: agilent ZORBAX Rx-C 8 (4.6mm×250mm,5.0μm)；
Mobile phase: dipotassium hydrogen phosphate buffer (2.7. 2.7g K) 2 HPO 4 +2.4mL triethylamine+800 mL water with H 3 PO 4 Adjust pH to 7.5) -acetonitrile (80: 20 A) is provided;
column temperature: 30 ℃;
detection wavelength: 220nm;
flow rate: 1.0mL/min;
sample injection amount: 20. Mu.L.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
The structure of the midinon intermediate compound I is confirmed:
high resolution mass spectrum of compound I: ESI-HRMS m/z=164.0712 [ M+H ]] + ；
1 H-NMR(400MHz,DMSO-d 6 )：9.72(d,J＝8.0Hz,1H)，8.36(d,J＝7.6Hz,2H)，7.21(d,J＝7.6Hz,2H)，4.50(d,J＝7.4Hz,1H)，2.30(s,3H)；
13 C NMR(100MHz,DMSO-d 6 ):δ200.3，187.8，154.1，142.1，124.2，63.6，29.5。
Preparation of milrinone intermediate compound I
Example 1
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.82 g,5.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (33.34 g,0.34 mol) in water (50 mL), α -bromoacetoacetal (SM-1 X=Br, 16.48g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.74g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I15.62 g in a yield of 95.8% and a purity of 99.96%.
Example 2
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.80 g,5.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (33.36 g,0.34 mol) in water (50 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.51g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 12.92g,0.105 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I14.77 g, yield 90.6% and purity 99.92%.
Example 3
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.83 g,5.00 mmol) was added to dimethyl sulfoxide (200 mL), and after stirring and mixing, a solution of KOAc (33.37 g,0.34 mol) in water (50 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.52g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 12.27g,0.10 mol) were added to the reaction mixture, followed by stirring and refluxing, filtering, and adding the filtrateExtracting with purified water (800 mL), ethyl acetate (250 mL. Times.2), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain milrinone intermediate compound I14.07 g, yield 87.5% and purity 99.86%.
Example 4
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.81 g,5.00 mmol) was added to dimethyl sulfoxide (200 mL), stirred and mixed, then a solution of KOAc (33.34 g,0.34 mol) in water (50 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.48g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 15.98g,0.13 mol) were added to the reaction mixture, stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a milrinone intermediate compound I15.49 g in a yield of 95.0% and a purity of 99.87%.
Example 5
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.83 g,5.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (33.35 g,0.34 mol) in water (50 mL), α -bromoacetoacetal (SM-1 X=Br, 16.50g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 17.22g,0.14 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I15.42 g in a yield of 94.6% and a purity of 99.76%.
Example 6
Pd (PPh) under argon protection at room temperature 3 ) 4 (3.48 g,3.00 mmol) was added to dimethyl sulfoxide (200 mL), stirred and mixed well, then a solution of KOAc (25.47 g,0.26 mol) in water (40 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.51g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.75g,0.12 mol) were added to the reaction mixture, stirred and refluxed to react, the reaction was completed, filtered, the filtrate was added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, and the organic phases were combined without any reactionDrying with sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 14.75g of milrinone intermediate compound I, with a yield of 90.5% and a purity of 99.88%.
Example 7
Pd (PPh) under argon protection at room temperature 3 ) 4 (3.48 g,3.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (24.52 g,0.25 mol) in water (40 mL), α -bromoacetoacetal (SM-1 X=Br, 16.49g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.76g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I14.25 g in a yield of 88.4% and a purity of 99.74%.
Example 8
Pd (PPh) under argon protection at room temperature 3 ) 4 (2.88 g,2.50 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (25.47 g,0.26 mol) in water (40 mL), α -bromoacetoacetal (SM-1 X=Br, 16.50g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.76g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I13.92 g in a yield of 87.6% and a purity of 99.82%.
Example 9
Pd (PPh) under argon protection at room temperature 3 ) 4 (8.06 g,7.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (44.15 g,0.45 mol) in water (65 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.48g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.75g,0.12 mol) were added to the reaction solution, stirred and refluxed, the reaction was completed, filtered, the filtrate was added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain milrinone15.52g of the intermediate compound I, the yield is 95.2%, and the purity is 99.82%.
Example 10
Pd (PPh) under argon protection at room temperature 3 ) 4 (8.05 g,7.00 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (45.17 g,0.46 mol) in water (70 mL), α -bromoacetoacetal (SM-1 X=Br, 16.51g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.77g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), extracted with ethyl acetate (250 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give milrinone intermediate compound I15.55 g in a yield of 95.4% and a purity of 99.72%.
Example 11
Pd (PPh) under argon protection at room temperature 3 ) 4 (8.65 g,7.50 mmol) was added to dimethyl sulfoxide (200 mL), after stirring and mixing, a solution of KOAc (44.16 g,0.45 mol) in water (65 mL), α -bromoacetoacetal (SM-1 X=Br, 16.47g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.76g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), ethyl acetate (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a milrinone intermediate compound I15.49 g in a yield of 95.0% and a purity of 99.75%.
Example 12
Pd (dppf) Cl under the protection of argon at room temperature 2 (3.64 g,5.00 mmol) was added to dimethyl sulfoxide (240 mL), and after stirring and mixing, a solution of KOAc (33.35 g,0.34 mol) in water (50 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.49g,0.10 mol) and 4-diethylpyridineborane (SM-2 R=CH) were added to the reaction mixture 2 CH 3 17.65g,0.12 mol), stirring and refluxing, filtering, adding the filtrate into purified water (750 mL), extracting with ethyl acetate (250 mL×2), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 15.27g of milrinone intermediate compound I with a yield of 93.7%, and purityThe degree was 99.91%.
Example 13
Pd (PPh) under argon protection at room temperature 3 ) 2 Cl 2 (3.52 g,5.00 mmol) was added to toluene (240 mL), and after stirring and mixing, a solution of KOAc (33.35 g,0.34 mol) in water (50 mL), alpha-iodoacetoacetal (SM-1 X=I, 21.28g,0.10 mol) and 4-diethylpyridineborane (SM-2 R=CH) were added to the reaction mixture 2 CH 3 17.64g,0.12 mol), stirring and refluxing, filtering, adding the filtrate into purified water (720 mL), extracting with ethyl acetate (250 mL×2), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and obtaining 15.35g of milrinone intermediate compound I with a yield of 94.2% and a purity of 99.89%.
Example 14
Pd (OAc) was then introduced under argon at room temperature 2 (PPh 3 ) 2 (3.73 g,5.00 mmol) was added to 1, 4-dioxane (250 mL), and after stirring and mixing, a solution of KOAc (33.35 g,0.34 mol) in water (50 mL), alpha-trifluoromethanesulfonic acid acetoacetal (SM-1 X=TfO, 23.42g,0.10 mol) and 4-diethylpyridineborane (SM-2 R=CH) were added to the reaction mixture 2 CH 3 17.66g,0.12 mol), stirring and refluxing, filtering, adding the filtrate into purified water (1000 mL), extracting with ethyl acetate (250 mL×2), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and obtaining 15.45g of milrinone intermediate compound I with a yield of 94.8% and a purity of 99.86%.
Example 15
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.82 g,5.00 mmol) was added to dimethyl sulfoxide (220 mL), and after stirring, K was added to the reaction mixture 2 CO 3 (46.97 g,0.34 mol) of water (50 mL), alpha-iodoacetoacetal (SM-1X=I, 21.19g,0.10 mol) and 4-pyridineboronic acid (SM-2R=OH, 14.74g,0.12 mol), stirring and refluxing the reaction, filtering, adding the filtrate into purified water (700 mL), extracting ethyl acetate (250 mL×2), merging the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain rice15.13g of the rinone intermediate compound I is obtained, the yield is 92.8%, and the purity is 99.87%.
Example 16
Pd is protected by argon under the room temperature condition 2 (dba) 3 (4.76 g,5.00 mmol) was added to isopropyl alcohol (250 mL), and after stirring and mixing, na was added to the reaction solution 3 PO 4 (55.75 g,0.34 mol) of water (50 mL), an alpha-trifluoromethanesulfonic acid ester acetoacetal (SM-1X=TfO, 23.40g,0.10 mol) and 4-pyridineboronic acid (SM-2R=OH, 14.75g,0.12 mol), stirring and refluxing the reaction, ending the reaction, filtering, adding the filtrate to purified water (750 mL), extracting ethyl acetate (250 mL. Times.2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, to obtain the milrinone intermediate compound I15.19 g in 93.2% yield with a purity of 99.85%.
Example 17
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.82 g,5.00 mmol) was added to acetonitrile (200 mL), and after stirring and mixing, cs was added to the reaction solution 2 CO 3 (97.72 g,0.30 mol) of water (45 mL), alpha-bromoacetoacetal (SM-1 x=br, 16.52g,0.10 mol) and 4-pyridineboronic acid (SM-2 r=oh, 14.75g,0.12 mol), stirring and refluxing the reaction, ending the reaction, filtering, adding the filtrate to purified water (1000 mL), extracting dichloromethane (250 ml×2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, to obtain 15.09g of milrinone intermediate compound i with a yield of 92.6% and a purity of 99.84%.
Example 18
Pd (dppf) Cl under the protection of argon at room temperature 2 (3.66 g,5.00 mmol) was added to purified water (200 mL), and after stirring, na was added to the reaction mixture 2 CO 3 (36.04 g,0.34 mol) of water (50 mL), alpha-bromoacetoacetal (SM-1X=Br, 16.52g,0.10 mol) and 4-pyridineboronic acid (SM-2R=OH, 14.77g,0.12 mol), stirring and refluxing, filtering, adding the filtrate into purified water (600 mL), extracting chloroform (250 mL×3), merging the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain midbody compound15.24g of I was obtained in 93.5% yield with a purity of 99.87%.
Example 19
Pd (OAc) was then introduced under argon at room temperature 2 (PPh 3 ) 2 (3.75 g,5.00 mmol) was added to N, N-dimethylformamide (170 mL), and after stirring and mixing, K was added to the reaction mixture 3 PO 4 (84.92 g,0.40 mol) of water (60 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.50g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.75g,0.12 mol), stirring and refluxing the reaction, ending the reaction, filtering, adding the filtrate to purified water (850 mL), extracting with ethyl acetate (250 mL. Times.2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 14.96g of milrinone intermediate compound I in a yield of 91.8% and a purity of 99.81%.
Example 20
Pd (PPh) under argon protection at room temperature 3 ) 4 (5.82 g,5.00 mmol) was added to ethanol (200 mL), after stirring and mixing, a solution of NaOAc (34.44 g,0.42 mol) in water (65 mL), alpha-bromoacetoacetal (SM-1 X=Br, 16.49g,0.10 mol) and 4-pyridineboronic acid (SM-2 R=OH, 14.76g,0.12 mol) were added to the reaction mixture, the reaction was stirred and refluxed, the reaction was completed, the filtrate was filtered, added to purified water (800 mL), methyl tert-butyl ether (250 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give milrinone intermediate compound I15.37 g in a yield of 94.3% and a purity of 99.92%.
Preparation of milrinone
Example 21
At room temperature, milrinone intermediate compound I (16.32 g,0.10 mol) and alpha-cyanoacetamide (11.78 g,0.14 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.54g of white crystal milrinone is obtained, the yield is 92.6%, and the purity is 99.98%.
Example 22
At room temperature, milrinone intermediate compound I (16.34 g,0.10 mol) and alpha-cyanoacetamide (9.26 g,0.11 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.05g of white crystal milrinone is obtained, the yield is 90.3%, and the purity is 99.95%.
Example 23
At room temperature, milrinone intermediate compound I (16.32 g,0.10 mol) and alpha-cyanoacetamide (8.42 g,0.10 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 17.85g of white crystal milrinone is obtained, the yield is 84.6%, and the purity is 99.83%.
Example 24
At room temperature, milrinone intermediate compound I (16.31 g,0.10 mol) and alpha-cyanoacetamide (14.28 g,0.17 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.31g of white crystal milrinone is obtained, the yield is 91.5%, and the purity is 99.91%.
Example 25
At room temperature, milrinone intermediate compound I (16.33 g,0.10 mol) and alpha-cyanoacetamide (15.14 g,0.18 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.16g of white crystal milrinone is obtained, the yield is 90.8%, and the purity is 99.76%.
Example 26
At room temperature, milrinone intermediate compound I (16.30 g,0.10 mol) and alpha-cyanoacetamide (11.77 g,0.14 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 11.5, stirred and refluxed for reaction, after TLC detection reaction is complete, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 17.43g of white crystal milrinone is obtained, the yield is 82.6%, and the purity is 98.83%.
Example 27
At room temperature, milrinone intermediate compound I (16.32 g,0.10 mol) and alpha-cyanoacetamide (11.75 g,0.14 mol) are added into ethanol (120 mL), stirred and mixed uniformly, 7.5mol/L sodium hydroxide solution is added dropwise to adjust the pH value to 13, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 5.0-5.5 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 17.26g of white crystal milrinone is obtained, the yield is 81.8%, and the purity is 99.78%.
Example 28
At room temperature, milrinone intermediate compound I (16.34 g,0.10 mol) and alpha-cyanoacetamide (11.78 g,0.14 mol) are added into methanol (160 mL), stirred and mixed uniformly, 7.0mol/L potassium hydroxide solution is added dropwise to adjust the pH value to 12, stirred and refluxed for reaction, after TLC detection reaction is completed, the reaction is completed, and the reaction solution is cooled to room temperature; regulating the pH value of the reaction solution to 6-7 by formic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.29g of white crystal milrinone is obtained, the yield is 91.4%, and the purity is 99.93%.
Example 29
At room temperature, milrinone intermediate compound I (16.32 g,0.10 mol) and alpha-cyanoacetamide (11.79 g,0.14 mol) are added into isopropanol (100 mL), stirred and mixed uniformly, 8.0mol/L barium hydroxide solution is added dropwise to adjust the pH value to 14, stirred and refluxed for reaction, after TLC detection reaction is complete, the reaction is completed, and the reaction solution is cooled to room temperature; adjusting the pH value of the reaction solution to 6-7 by hydrochloric acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.16g of white crystal milrinone is obtained, the yield is 90.8%, and the purity is 99.92%.
Example 30
Sodium ethoxide is added into ethanol (100 mL) at room temperature, and the pH value of the solution is regulated to 13 while stirring; after milrinone intermediate compound I (16.33 g,0.10 mol) and alpha-cyanoacetamide (11.76 g,0.14 mol) are added into the ethanol solution, sodium ethoxide is added into the mixture while stirring and mixing the mixture uniformly to adjust the pH value of the solution to 13; stirring and refluxing for reaction, and cooling the reaction liquid to room temperature after TLC detection reaction is completed; adjusting the pH value of the reaction solution to 6-7 by hydrochloric acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.24g of white crystal milrinone is obtained, the yield is 91.2%, and the purity is 99.94%.
Example 31
Sodium methoxide was added to methanol (80 mL) at room temperature with stirring, and the pH of the solution was adjusted to 12; milrinone intermediate compound I (16.33 g,0.10 mol) and alpha-cyanoacetamide (11.79 g,0.14 mol) are added into the methanol solution, and sodium methoxide is added into the mixture while stirring and mixing the mixture to adjust the pH value of the solution to 12; stirring and refluxing for reaction, and cooling the reaction liquid to room temperature after TLC detection reaction is completed; the pH value of the reaction solution is regulated to 6-7 by hydrobromic acid, stirred and crystallized, and white solid is separated out; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.07g of white crystal milrinone is obtained, the yield is 90.4%, and the purity is 99.93%.
Example 32
Sodium isopropoxide is added into isopropanol (80 mL) at room temperature, and the pH value of the solution is adjusted to 13 while stirring; milrinone intermediate compound I (16.30 g,0.10 mol) and alpha-cyanoacetamide (11.77 g,0.14 mol) are added into the isopropanol solution, and sodium isopropoxide is added into the solution to adjust the pH value of the solution to 13 while stirring and mixing the mixture uniformly; stirring and refluxing for reaction, and cooling the reaction liquid to room temperature after TLC detection reaction is completed; the pH value of the reaction solution is regulated to 6-7 by hydroiodic acid, and the reaction solution is stirred for crystallization, so that white solid is separated out; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.16g of white crystal milrinone is obtained, the yield is 90.8%, and the purity is 99.90%.
Example 33
Sodium tert-butoxide (90 mL) was added to tert-butanol at room temperature with stirring, and the pH of the solution was adjusted to 12; milrinone intermediate compound I (16.31 g,0.10 mol) and alpha-cyanoacetamide (11.78 g,0.14 mol) are added into the tertiary butanol solution, and the tertiary butanol sodium is added to adjust the pH value of the solution to 12 while stirring and mixing uniformly; stirring and refluxing for reaction, and cooling the reaction liquid to room temperature after TLC detection reaction is completed; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.07g of white crystal milrinone is obtained, the yield is 90.4%, and the purity is 99.91%.
Example 34
Sodium hydroxide is added into ethanol (120 mL) at room temperature, stirring is carried out while adding, and the pH value of the solution is regulated to 14; milrinone intermediate compound I (16.33 g,0.10 mol) and alpha-cyanoacetamide (11.77 g,0.14 mol) are added into the ethanol solution, and sodium hydroxide is added to adjust the pH value of the solution to 14 while stirring and mixing uniformly; stirring and refluxing for reaction, and cooling the reaction liquid to room temperature after TLC detection reaction is completed; regulating the pH value of the reaction solution to 6-7 by acetic acid, stirring for crystallization, and separating off white solid; after crystallization is completed, suction filtration is carried out, and a filter cake is dried in vacuum, so that 19.35g of white crystal milrinone is obtained, the yield is 91.7%, and the purity is 99.95%.
Claims (9)
1. The preparation method of milrinone is characterized by comprising the following steps of: at room temperature, milrinone intermediate compound I,αAdding cyanoacetamide into an organic solvent, stirring uniformly, performing temperature control reaction in an alkaline environment, cooling the reaction solution to room temperature, crystallizing, filtering and drying to obtain milrinone, wherein the synthetic route is as follows:
2. the method for preparing milrinone according to claim 1, wherein the intermediate compound I is a compound prepared from milrinone andαthe molar ratio of cyanoacetamide to feed is 1:1.1 to 1.7.
3. The method for preparing milrinone according to claim 1, wherein the organic solvent is one or a combination of methanol, ethanol, isopropanol and tert-butanol.
4. The method for preparing milrinone according to claim 1, wherein 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 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; the pH value of the alkaline environment is 12-14.
5. The method for preparing milrinone according to claim 1, wherein the temperature-controlled reaction is a temperature-controlled reflux reaction.
6. The method for preparing milrinone according to claim 1, wherein the crystallization method is to add acid to the reaction solution to adjust the pH value, and stir and crystallize; the acid is one or the combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; and adding acid to adjust the pH value to 6-7.
7. The method for preparing milrinone according to claim 1, characterized in that the method for preparing milrinone intermediate compound i comprises the following steps: under the protection of inert gas, under the condition of room temperature, adding a catalyst into a reaction solvent, stirring and uniformly mixing, adding an aqueous solution of alkali, a compound SM-1 and a compound SM-2 into the reaction solvent, stirring and controlling the temperature to react, finishing the reaction, filtering, adding filtrate into purified water, extracting an extractant, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a milrinone intermediate compound I, wherein the synthetic route is as follows:
wherein X is one of I, tfO and Br; r is OH, CH 2 CH 3 One of them.
8. The method for preparing milrinone according to claim 7, wherein the catalyst is Pd (PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Pd 2 (dba) 3 、Pd(OAc) 2 (PPh 3 ) 2 One or a combination thereof; the reaction solvent is ethanol, isopropanol, acetonitrile, 1, 4-dioxane, water, toluene,N,N-one of dimethylformamide, dimethyl sulfoxide or a combination thereof.
9. The method for preparing milrinone according to claim 7, wherein the alkali is K 2 CO 3 、Na 2 CO 3 、Cs 2 CO 3 、K 3 PO 4 、Na 3 PO 4 One or a combination of NaOAc, KOAc; the feeding mole ratio of the compound SM-1 to the compound SM-2 to the base to the catalyst is 1: 1.05-1.3: 2.6-4.5: 0.03 to 0.07.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364776A (en) * | 1991-10-04 | 1994-11-15 | Merck & Co., Inc. | Method of hydroxylating 3-[3-(5-ethyl-2-methoxy-6-methylpyridyl)methyl]amino-5-ethyl-6-methyl-2(1H)-pyridinone with liver slices |
| CN101143844A (en) * | 2007-01-16 | 2008-03-19 | 张刘森 | Method of preparing milrinone lactate |
| CN101157590A (en) * | 2007-11-23 | 2008-04-09 | 武汉大学 | Method for preparing alpha-aryl carbonyl compound |
| CN104387320A (en) * | 2014-09-28 | 2015-03-04 | 湖州展望药业有限公司 | Preparation method for high-purity milrinone |
| CN105530814A (en) * | 2013-07-09 | 2016-04-27 | 拜耳作物科学股份公司 | Use of selected pyridone carboxamides or salts thereof as active substances against abiotic plant stress |
| CN107698501A (en) * | 2017-10-25 | 2018-02-16 | 遵义医学院 | The preparation technology of the hydroxy niacin of 5,6 dimethyl 2 |
-
2019
- 2019-03-20 CN CN201910214370.8A patent/CN111718295B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364776A (en) * | 1991-10-04 | 1994-11-15 | Merck & Co., Inc. | Method of hydroxylating 3-[3-(5-ethyl-2-methoxy-6-methylpyridyl)methyl]amino-5-ethyl-6-methyl-2(1H)-pyridinone with liver slices |
| CN101143844A (en) * | 2007-01-16 | 2008-03-19 | 张刘森 | Method of preparing milrinone lactate |
| CN101157590A (en) * | 2007-11-23 | 2008-04-09 | 武汉大学 | Method for preparing alpha-aryl carbonyl compound |
| CN105530814A (en) * | 2013-07-09 | 2016-04-27 | 拜耳作物科学股份公司 | Use of selected pyridone carboxamides or salts thereof as active substances against abiotic plant stress |
| CN104387320A (en) * | 2014-09-28 | 2015-03-04 | 湖州展望药业有限公司 | Preparation method for high-purity milrinone |
| CN107698501A (en) * | 2017-10-25 | 2018-02-16 | 遵义医学院 | The preparation technology of the hydroxy niacin of 5,6 dimethyl 2 |
Non-Patent Citations (4)
| Title |
|---|
| A convenient synthesis of nicotinate esters from 3-cyanopyridones;John B. Paine;《J. Heterocyclic Chem.》;19870430;第24卷;第351-355页 * |
| Ni-Catalyzed Mild Arylation of a-Halocarbonyl Compounds with Arylboronic Acids;Chao Liu等;《Org. Lett.》;20071204;第9卷(第26期);第5601-5604页 * |
| Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acids;Lukas J. Goossen;《Chem. Commun.》;20010321;第669-670页 * |
| 何仁等编著.Suzuki偶联反应.《金属有机化学》.上海：华东理工大学出版社,2007,第294-300页. * |
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