CN113493410B - Preparation process of milrinone - Google Patents

Preparation process of milrinone Download PDF

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CN113493410B
CN113493410B CN202010201253.0A CN202010201253A CN113493410B CN 113493410 B CN113493410 B CN 113493410B CN 202010201253 A CN202010201253 A CN 202010201253A CN 113493410 B CN113493410 B CN 113493410B
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milrinone
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cyanoacetamide
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CN113493410A (en
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鲍广龙
张乃华
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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, and belongs to the technical field of drug synthesis. The method takes 1- (4-pyridyl) -2-acetone as a raw material to react with alpha- (substituted methylene) cyano acetamide under alkaline condition by heating, thus obtaining milrinone. The method for preparing milrinone has the advantages of simple operation, high safety and high yield, and is suitable for industrial scale-up production. The obtained milrinone finished product has the appearance and purity reaching the standards.

Description

Preparation process of milrinone
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of 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 states, 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 hypocardiac discharge syndrome after cardiac surgical extracorporeal circulation, relieving bypass vasospasm, improving cardiac function and anti-inflammatory response in heart in situ transplant patients, improving visceral blood perfusion and the like. The chemical structural formula is as follows:
The product is a homologous drug of amrinone (Amrinone), is a positive inotropic drug of non-digitalis cardiac glycoside and non-catecholamine, can selectively inhibit phosphodiesterase III (PDE III) in myocardial cells, change the transportation of calcium ions inside and outside cells, strengthen myocardial contractility, 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 process of milrinone mainly comprises the following steps:
One approach 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.): the method takes 4-methylpyridine as a starting material to prepare 1- (4-pyridyl) -2-acetone, the reaction can be realized through two paths, the first path is to react with ethyl acetate under the condition of n-butyllithium or phenyllithium, but the reaction condition is strict, the water is easy to generate exothermic reaction when meeting oxygen, the air is easy to burn, once the thermal expansion is easy to cause explosion, the operation is difficult, the price is relatively high, and the risk of generating benzene with high toxicity is generated in the reaction process, so the method is not suitable for industrial production. The second path is to react with acetyl chloride at room temperature for 16h, and the reaction time is too long although the reaction condition is mild. Meanwhile, the pH value of the system is regulated by saturated sodium carbonate in the post-treatment, and the water phase which is more than 10 times of the reaction volume is required to be consumed, so that the operation is difficult, 3 times of extraction and reduced pressure concentration are used in the whole post-treatment, the post-treatment is more complicated, the reaction time in the second step is longer, and the production cost is increased.
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. In the process, a Soxhlet extractor is adopted for extraction and recrystallization, and the operation is complicated; in the final cyclization step, malononitrile is applied to be more toxic than α -cyanoacetamide and more expensive than α -cyanoacetamide, so that the production process using malononitrile is less safe and the production cost is also higher.
Another approach is to use a "convergent" synthetic route (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 the crude product is recrystallized to obtain fine milrinone. The method needs three steps of reactions to prepare milrinone, and the milrinone cannot be realized by a one-pot method, so that the route is relatively long, the yield of the final reaction is lower by 34 percent, compared with the yield of 70 percent of other routes, the method has no obvious advantage, and the prepared milrinone has reddish color and cannot be removed by refining.
Summarizing the preparation process of milrinone in the prior art, firstly preparing 1- (4-pyridyl) -2-acetone by using 4-methylpyridine, and then preparing milrinone by using 1- (4-pyridyl) -2-acetone as a raw material. Chen Shuangwei et al (Milrinone Synthesis process research, chinese Journal of MEDICINAL CHEMISTRY, VOL.19NO.4P.241, aug 2009Sum 90) report a preparation method of Milrinone, 4-methylpyridine is used as a raw material to prepare 1- (4-pyridyl) -2-propanone first, and then 1- (4-pyridyl) -2-propanone is used to prepare Milrinone, wherein the final yield is only 52.9%. The reaction route is as follows:
The raw material 1- (4-pyridyl) -2-acetone is light yellow liquid, and according to the report of (1- (4-pyridyl) -2-acetone synthesis process improvement, journal of Chemical Industry & Engineering, vol.30No.4Aug, 2009), the 1- (4-pyridyl) -2-acetone needs to be distilled at 100-102 ℃/267Pa (2 mmHg), the operation condition is harsh, and the yield is not high. In industrial mass production, high-temperature reduced pressure distillation has high requirements on process operation conditions and equipment, low operation safety and low yield and purity. On the other hand, compared with the solid raw material, the 1- (4-pyridyl) -2-acetone in a liquid state is taken as the raw material for preparation, the operation is difficult, and the feeding amount is not easy to control.
In summary, the reported milrinone preparation method has a plurality of defects in the aspects of safe process, simple operation and the like, so that the research and the search of a reaction route suitable for industrial production of milrinone are still the problems to be solved at present, and the reaction route has the advantages of mild reaction conditions, simple operation process, high product yield, high purity and low production cost.
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 utilizes an intermediate compound I to react with alpha- (substituted methylene) cyano acetamide, namely SM-2 to obtain milrinone, wherein the reaction formula is as follows:
wherein X is one of C1-C6 alkoxy and dimethylamino; the C1-C6 alkoxy group is preferably methoxy, ethoxy or propoxy.
A preparation method of milrinone comprises the following steps:
Adding an intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to regulate the pH of the solution, controlling the temperature to react, adding acid to regulate the pH of the solution after the reaction is finished, and stirring to separate out solids to obtain milrinone.
Preferably, the further step of preparing milrinone comprises:
Adding an intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH of the solution, controlling the temperature until the reaction is finished, adding acid to adjust the pH of the solution, precipitating solid, and filtering to obtain milrinone.
Preferably, the feeding mole ratio of the intermediate compound I to the alpha- (substituted methylene) cyanoacetamide is 1:1.1 to 1.7, preferably 1:1.3.
Preferably, the reaction solvent is one or two of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.
Preferably, the ratio of the mass volume of the intermediate compound I to the reaction solvent is 1:5 to 10, wherein the mass is in g and the volume is in ml.
Preferably, the alkali is an inorganic alkali or an organic alkali, wherein the inorganic alkali is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic alkali can be 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; sodium hydroxide is preferred.
Preferably, the pH value of the alkaline regulating solution is 12-14.
Preferably, the temperature-controlled reaction temperature is the temperature at which the reaction liquid reaches reflux.
Preferably, the acid is one or a combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, preferably acetic acid.
Preferably, the pH value of the solution is adjusted to 6-7 by adding acid.
In one embodiment, when R is dimethylamino, adding acid to regulate the pH value of the solution to separate out solid, filtering, pulping the filter cake with purified water of 40-50 deg.c, and filtering to obtain white solid milrinone.
The intermediate compound I of the present invention can be prepared by:
Under the action of acetyl chloride and acetic anhydride, 4-methylpyridine, namely SM-1, is taken as a raw material to prepare a solid form intermediate compound I, and the reaction formula is as follows:
the preparation of intermediate I comprises the following steps:
adding 4-methylpyridine and acetyl chloride into a solvent, stirring for reaction, adding alkali to regulate the pH of a reaction solution after the reaction is finished, collecting an organic phase, performing reduced pressure distillation, recovering 4-methylpyridine, obtaining a concentrated viscous liquid, and performing aftertreatment to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I.
Preferably, the further step of preparing intermediate I comprises:
Adding 4-methylpyridine into dichloromethane, adding acetyl chloride, and performing temperature control reaction to finish the reaction; adding purified water, adding alkali while stirring to adjust the pH of the reaction solution, separating, collecting an organic phase, extracting with aqueous dichloromethane, mixing the organic phases, drying with a drying agent, filtering, distilling the filtrate under reduced pressure at a controlled temperature until no fraction flows out, and recovering 4-methylpyridine; the concentrated solution is continuously heated, decompressed and concentrated to obtain viscous liquid, and is post-treated to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I.
Preferably, the mass-volume ratio of the 4-methylpyridine to the dichloromethane is 1:1.5-4, wherein the mass is calculated in g and the volume is calculated in ml.
Preferably, the feeding mole ratio of the 4-methylpyridine to the acetyl chloride is 1:1.2-3, preferably 1:2.2.
In a preferred scheme, the acetyl chloride can be added at a controlled temperature or not, the acetyl chloride is added at a controlled temperature, and the temperature can be set to be 15-25 ℃.
Preferably, the temperature-controlled reaction temperature is 20-30 ℃.
Preferably, the temperature of the purified water is controlled to be 0-20 ℃.
Preferably, the alkali is an inorganic alkali or an organic alkali, wherein the inorganic alkali is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic alkali can be alkali or an aqueous solution thereof; the organic base is one or a combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide; sodium hydroxide is preferred.
Preferably, the pH value of the reaction solution is adjusted to 12-14 by adding alkali.
Preferably, the temperature of the reduced pressure distillation is 50-60 ℃.
Preferably, the temperature of the continuous heating, decompressing and concentrating is 70-80 ℃.
In a preferred embodiment, the post-treatment steps are: and respectively adding ethyl acetate and acetic anhydride into the viscous liquid, stirring to separate out solid, filtering, leaching and drying after the solid is separated out, thus obtaining the solid compound intermediate I.
Preferably, the amount of ethyl acetate is 2 to 5 times the volume of the viscous liquid.
Preferably, the acetic anhydride is added by selecting a temperature control process, wherein the temperature control temperature is 0-25 ℃.
Preferably, the feeding amount of the acetic anhydride is 5-10 times of the volume of the viscous liquid.
Preferably, the eluting solvent is absolute ethyl alcohol.
When SM-2 is 2-cyano-3-alkoxy acrylamide, namely X is alkoxy, the invention can be prepared by reacting alpha-cyano acetamide with trialkyl orthoformate, and the reaction formula is as follows:
wherein R is C1-C6 alkyl, preferably methyl, ethyl and propyl.
In a preferred embodiment, when R is ethyl, the specific reaction steps for preparing SM-2 are:
Adding alpha-cyanoacetamide and triethyl orthoformate into a mixed solvent of acetic anhydride and glacial acetic acid, controlling the temperature to be 40-45 ℃ for reaction for 3-4 hours, adding absolute ethyl alcohol to quench acetic anhydride, stirring for 10-15 minutes, controlling the temperature to be 50-60 ℃ and concentrating under reduced pressure until no fraction flows out, continuously heating to be 75-80 ℃ and concentrating under reduced pressure until the mixture is dry, and recrystallizing to obtain white solid 2-cyano-3-ethoxyacrylamide.
Preferably, the feeding mole ratio of the alpha-cyano acetamide to the triethyl orthoformate is 1:1.1-2.
Preferably, the feeding mass ratio of the alpha-cyano acetamide to the mixed solvent (m Acetic anhydride ：m Glacial acetic acid =1:10) is 1:5-6.
Preferably, the recrystallization system is an n-hexane-ethanol system, and the volume ratio of n-hexane to ethanol is preferably 3:1.
When R is methoxy or propoxy, referring to the preparation method of the 2-cyano-3-ethoxyacrylamide, alpha-cyanoacetamide can be utilized to react with trimethyl orthoformate or tripropyl orthoformate to respectively prepare the 2-cyano-3-methoxyacrylamide or the 2-cyano-3-propoxyacrylamide.
In one embodiment, when SM-2 is 2-cyano-3-dimethylaminoacrylamide, i.e., R is dimethylamino, the invention can be prepared by reacting α -cyanoacetamide with N, N-dimethylformamide dimethyl acetal, i.e., DMF-DMA, with the following reaction formula:
preferably, the specific reaction steps are:
Adding alpha-cyanoacetamide and N, N-dimethylformamide dimethyl acetal into 1, 4-dioxane, controlling the temperature to be 95-100 ℃ for reaction, adding the reaction solution into purified water at 0-5 ℃ after the detection reaction is finished, and separating out solids; continuously stirring and crystallizing for 1-2 hours, filtering, dissolving the obtained filter cake with dilute hydrochloric acid solution, washing with dichloromethane, adding sodium hydroxide solution into a water layer to adjust the pH value to 11-12, continuously stirring and crystallizing for 1-2 hours, and filtering to obtain the 2-cyano-3-dimethylamino acrylamide.
Preferably, the molar feed ratio of the alpha-cyanoacetamide to the N, N-dimethylformamide dimethyl acetal is 1:1.1-2.5.
Preferably, the mass-volume ratio of the alpha-cyanoacetamide to the 1, 4-dioxane feed is 1:5-10, wherein the mass is in g and the volume is in ml.
The invention has the beneficial effects that:
The invention provides a novel milrinone preparation method, which uses a solid intermediate compound 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone to replace liquid 1- (4-pyridyl) -2-acetone in the prior art to prepare milrinone, and has simple operation and easy control of the feeding amount; compared with an intermediate compound 1- (4-pyridyl) -2-acetone obtained by high-temperature reduced pressure distillation, the intermediate compound disclosed by the invention is simple and easy to obtain, and the purity of the prepared intermediate compound I is high by utilizing the recrystallization of acetic anhydride; compared with the prior art, the milrinone preparation process shortens the process route, is simple and convenient to operate and safe, 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 invention adopts HPLC to measure the purity of milrinone, and the chromatographic conditions are as follows:
Chromatographic column: agilent ZORBAX Rx-C 8 (4.6 mm. Times.250 mm,5.0 μm);
Mobile phase: dipotassium phosphate buffer (2. g K 2HPO4 +2.4ml triethylamine+800 ml water, pH adjusted to 7.5 with H 3PO4) -acetonitrile (80:20);
column temperature: 30 ℃;
detection wavelength: 220nm;
Flow rate: 1.0ml/min;
sample injection amount: 20 μl.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 11 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
4-Methylpyridine (93.08 g,1.0 mol) is added into methylene dichloride (200 ml), acetyl chloride (172.72 g,2.2 mol) is added at the temperature of 15-20 ℃, the reaction is carried out for 5 hours at the temperature of 20-30 ℃ after the addition is finished; adding purified water (400 ml) at the temperature of 10-15 ℃, adding sodium hydroxide solution (about 7.5 mol/ml) while stirring to adjust the pH value of the reaction liquid to 13-14, separating the liquid, collecting an organic phase, extracting aqueous phase dichloromethane (100 ml multiplied by 2), merging the organic phases, drying anhydrous sodium sulfate, filtering, carrying out reduced pressure distillation on the filtrate at the temperature of 50-60 ℃ until no fraction flows out, continuously heating the concentrated solution at the temperature of 70-80 ℃ and carrying out reduced pressure concentration to obtain viscous liquid (55.85 g of recovered 4-methylpyridine, and the recovery rate is 60%); adding ethyl acetate (45 ml) into the viscous liquid, adding acetic anhydride (110 ml) at the temperature of 0-10 ℃, stirring to precipitate solid, filtering, eluting with absolute ethyl alcohol (50 ml multiplied by 2), and drying to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I, wherein the yield is 93.5% (calculated by the actual 4-methylpyridine participating in the reaction, namely the input quantity is subtracted from the recovery quantity); the purity is 99.85 percent.
Example 21 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
4-Methylpyridine (93.12 g,1.0 mol) is added into methylene dichloride (150 ml), acetyl chloride (94.24 g,1.2 mol) is added at the temperature of 20-25 ℃, the reaction is carried out for 6 hours at the temperature of 20-30 ℃ after the addition is finished; adding purified water (400 ml) at the temperature of 0-10 ℃, adding sodium hydroxide solution (about 7.5 mol/ml) while stirring to adjust the pH value of the reaction liquid to 13-14, separating the liquid, collecting an organic phase, extracting aqueous phase dichloromethane (100 ml multiplied by 2), merging the organic phases, drying anhydrous sodium sulfate, filtering, carrying out reduced pressure distillation on the filtrate at the temperature of 50-60 ℃ until no fraction flows out, continuously heating the concentrated solution at the temperature of 70-80 ℃ and carrying out reduced pressure concentration to obtain viscous liquid (recovery rate of 57.73g of 4-methylpyridine and recovery rate of 62%); adding ethyl acetate (40 ml) into the viscous liquid, adding acetic anhydride (100 ml) at the temperature of 10-15 ℃, stirring to precipitate solid, filtering, eluting with absolute ethyl alcohol (50 ml multiplied by 2), and drying to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I, wherein the yield is 90.4% (calculated by the actual 4-methylpyridine participating in the reaction, namely the input quantity is subtracted by the recovery quantity); the purity was 99.78%.
Example 31 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
Adding 4-methylpyridine (93.07 g,1.0 mol) into dichloromethane (300 ml), controlling the temperature to be 20-25 ℃, adding acetyl chloride (235.54 g,3 mol), and reacting for 5 hours at the temperature to be 20-30 ℃ after the addition is finished; adding purified water (500 ml) at 15-20 ℃, adding sodium hydroxide solution (about 7.5 mol/ml) while stirring to adjust the pH value of the reaction liquid to 13-14, separating the liquid, collecting an organic phase, extracting aqueous phase dichloromethane (150 ml multiplied by 2), merging the organic phases, drying anhydrous sodium sulfate, filtering, carrying out reduced pressure distillation on the filtrate at 50-60 ℃ until no fraction flows out, continuously heating the concentrated solution at 70-80 ℃ and concentrating the concentrated solution at reduced pressure to obtain viscous liquid (recovery rate of 54.91g of 4-methylpyridine and recovery rate of 59%); adding ethyl acetate (50 ml) into the viscous liquid, adding acetic anhydride (115 ml) at the temperature of 20-25 ℃, stirring to precipitate solid, filtering, eluting with absolute ethyl alcohol (50 ml multiplied by 2), and drying to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I, wherein the yield is 918% (calculated by the actual 4-methylpyridine participating in the reaction, namely the input quantity is subtracted by the recovery quantity); the purity was 99.82%.
Example 41 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
4-Methylpyridine (93.05 g,1.0 mol) and acetyl chloride (172.75 g,2.2 mol) are added into methylene dichloride (250 ml), and the reaction is carried out for 5 hours at the temperature of 20-30 ℃ after the addition is finished; adding purified water (500 ml) into the reaction solution, adding sodium hydroxide solution (about 7.5 mol/ml) while stirring to adjust the pH value of the reaction solution to 12-13, separating the solution, collecting an organic phase, extracting aqueous phase dichloromethane (150 ml multiplied by 2), combining the organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, carrying out reduced pressure distillation on the filtrate at a temperature of 50-60 ℃ until no fraction flows out, continuously heating the concentrated solution at 70-80 ℃ and concentrating the concentrated solution at reduced pressure to obtain viscous liquid (55.83 g of recovered 4-methylpyridine, and the recovery rate is 60%); adding ethyl acetate (50 ml) into the viscous liquid, adding acetic anhydride (115 ml) at the temperature of 20-25 ℃, stirring to precipitate solid, filtering, eluting with absolute ethyl alcohol (50 ml multiplied by 2), and drying to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate compound I, wherein the yield is 90.2% (calculated by the actual 4-methylpyridine participating in the reaction, namely the input quantity is subtracted by the recovery quantity); the purity was 99.87%.
EXAMPLE 5 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.04 g,1.0 mol) and triethyl orthoformate (162.83 g,1.1 mol) are added into a mixed solvent of acetic anhydride and glacial acetic acid (415.84 g, m Acetic anhydride :m Glacial acetic acid =1:10), after the reaction is carried out for 3 hours at the temperature of 40-45 ℃, absolute ethyl alcohol (300 ml) is added to quench acetic anhydride, after stirring for 10-15 minutes, the mixture is concentrated under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, the mixture is continuously heated to 75-80 ℃ and concentrated under reduced pressure until the mixture is dried, normal hexane-ethyl alcohol (500 ml, V n-hexane :V ethanol =3:1) is recrystallized, and white solid 2-cyano-3-ethoxyacrylamide is obtained, the yield is 91.4%, and the purity is 99.45%.
EXAMPLE 6 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.06 g,1.0 mol) and triethyl orthoformate (236.84 g,1.6 mol) are added into a mixed solvent of acetic anhydride and glacial acetic acid (456.58 g, m Acetic anhydride :m Glacial acetic acid =1:10), after the reaction is carried out for 4 hours at the temperature of 40-45 ℃, absolute ethyl alcohol (350 ml) is added to quench acetic anhydride, after stirring for 10-15 minutes, the mixture is concentrated under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, the mixture is continuously heated to 75-80 ℃ and concentrated under reduced pressure until the mixture is dried, normal hexane-ethyl alcohol (500 ml, V n-hexane :V ethanol =3:1) is recrystallized, and white solid 2-cyano-3-ethoxyacrylamide is obtained, the yield is 94.2%, and the purity is 99.68%.
EXAMPLE 7 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.03 g,1.0 mol) and triethyl orthoformate (296.08 g,2.0 mol) are added into a mixed solvent of acetic anhydride and glacial acetic acid (498.03 g, m Acetic anhydride :m Glacial acetic acid =1:10), after the reaction is carried out for 4 hours at the temperature of 40-45 ℃, absolute ethyl alcohol (400 ml) is added to quench acetic anhydride, after stirring for 10-15 minutes, the mixture is concentrated under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, the mixture is continuously heated to 75-80 ℃ and concentrated under reduced pressure until the mixture is dried, normal hexane-ethyl alcohol (500 ml, V n-hexane :V ethanol =3:1) is recrystallized, and white solid 2-cyano-3-ethoxyacrylamide is obtained, the yield is 93.8%, and the purity is 99.57%.
EXAMPLE 8 preparation of alpha- (methoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.05 g,1.0 mol) and trimethyl orthoformate (169.63 g,1.6 mol) are added into a mixed solvent of acetic anhydride and glacial acetic acid (456.54 g, m Acetic anhydride :m Glacial acetic acid =1:10), after the reaction is carried out for 4 hours at the temperature of 40-45 ℃, absolute ethyl alcohol (350 ml) is added to quench acetic anhydride, after stirring for 10-15 minutes, the mixture is concentrated under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, the mixture is continuously heated to 75-80 ℃ and concentrated under reduced pressure until dryness, n-hexane-ethyl alcohol (500 ml, V n-hexane :V ethanol =3:1) is recrystallized, and white solid 2-cyano-3-methoxy acrylamide is obtained, the yield is 93.8%, and the purity is 99.65%.
EXAMPLE 9 preparation of alpha- (propoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.05 g,1.0 mol) and tripropyl orthoformate (304.07 g,1.6 mol) are added into a mixed solvent of acetic anhydride and glacial acetic acid (456.52 g, m Acetic anhydride :m Glacial acetic acid =1:10), after the reaction is carried out for 4 hours at the temperature of 40 to 45 ℃, absolute ethyl alcohol (400 ml) is added to quench acetic anhydride, after stirring for 10 to 15 minutes, the mixture is concentrated under reduced pressure at the temperature of 50 to 60 ℃ until no fraction flows out, the mixture is continuously heated to 75 to 80 ℃ and concentrated under reduced pressure until the mixture is dried, n-hexane-ethyl alcohol (500 ml, V n-hexane :V ethanol =3:1) is recrystallized, and white solid 2-cyano-3-propoxyacrylamide is obtained, the yield is 93.5 percent, and the purity is 99.62 percent.
EXAMPLE 10 alpha- (N, N-dimethylaminomethyl) cyanoacetamide
Alpha-cyanoacetamide (83.05 g,1.0 mol) and N, N-dimethylformamide dimethyl acetal (130.94 g,1.1 mol) are added into 1, 4-dioxane (450 ml), the temperature is controlled to be 95-100 ℃ for reaction, after the reaction is detected, the reaction solution is added into purified water (600 ml) with the temperature of 0-5 ℃ for solid precipitation; stirring and crystallizing for 1 hour, filtering, dissolving the obtained filter cake with dilute hydrochloric acid solution (300 ml), washing with dichloromethane (100 ml multiplied by 2), adding sodium hydroxide solution into a water layer to adjust the pH value to 11-12, stirring and crystallizing for 1 hour, filtering to obtain 2-cyano-3-dimethylaminoacrylamide with the yield of 92.4% and the purity of 99.38%.
EXAMPLE 11 alpha- (N, N-dimethylaminomethyl) cyanoacetamide
Alpha-cyanoacetamide (83.02 g,1.0 mol) and N, N-dimethylformamide dimethyl acetal (214.22 g,1.8 mol) are added into 1, 4-dioxane (600 ml), the temperature is controlled to be 95-100 ℃ for reaction, after the reaction is detected, the reaction solution is added into purified water (800 ml) with the temperature of 0-5 ℃ for solid precipitation; stirring and crystallizing for 2 hours, filtering, dissolving the obtained filter cake with dilute hydrochloric acid solution (300 ml), washing with dichloromethane (100 ml multiplied by 2), adding sodium hydroxide solution into a water layer to adjust the pH value to 11-12, stirring and crystallizing for 2 hours, filtering to obtain 2-cyano-3-dimethylaminoacrylamide with the yield of 94.3% and the purity of 99.58%.
EXAMPLE 12 alpha- (N, N-dimethylaminomethyl) cyanoacetamide
Alpha-cyanoacetamide (83.05 g,1.0 mol) and N, N-dimethylformamide dimethyl acetal (297.53 g,2.5 mol) are added into 1, 4-dioxane (800 ml), the temperature is controlled to be 95-100 ℃ for reaction, after the reaction is detected, the reaction solution is added into purified water (1000 ml) with the temperature of 0-5 ℃ for solid precipitation; stirring and crystallizing for 2 hours, filtering, dissolving the obtained filter cake with dilute hydrochloric acid solution (300 ml), washing with dichloromethane (100 ml multiplied by 2), adding sodium hydroxide solution into a water layer to adjust the pH value to 11-12, stirring and crystallizing for 2 hours, filtering to obtain 2-cyano-3-dimethylaminoacrylamide with the yield of 93.6% and the purity of 99.42%.
Example 13 preparation of milrinone
Intermediate compound I (177.04 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (182.06 g,1.3 mol) are added into ethanol (1200 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 93.4% and the purity is 99.97%.
Example 14 preparation of milrinone
Intermediate compound I (177.06 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (154.05 g,1.1 mol) are added into methanol (900 ml), and after being stirred evenly, 7.0mol/L potassium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding dilute hydrochloric acid to adjust the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 92.5% and the purity is 99.93%.
Example 15 preparation of milrinone
Intermediate compound I (177.01 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (140.03 g,1.0 mol) are added into ethanol (900 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 88.5% and the purity is 99.90%.
Example 16 preparation of milrinone
Intermediate compound I (177.02 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (238.12 g,1.7 mol) are added into ethanol (1500 ml), and after uniform stirring, sodium ethoxide is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, regulating the pH value of the solution to 6-7 by hydrobromic acid, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 92.7% and the purity is 99.95%.
Example 17 preparation of milrinone
Intermediate compound I (177.08 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (252.03 g,1.8 mol) are added into ethanol (1500 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; reflux reaction under controlled temperature, cooling the reaction liquid to room temperature, adding acetic acid to regulate pH value to 6-7, stirring to separate out solid, filtering and drying to obtain white solid milrinone with yield of 91.8% and purity of 99.92%
Example 18 preparation of milrinone
Intermediate compound I (177.03 g,1.0 mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (180.74 g,1.3 mol) are added into ethanol (1200 ml), and after being stirred uniformly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering, pulping a filter cake by using purified water (500 ml) at 40-50 ℃, filtering, and drying to obtain white-like solid milrinone, wherein the yield is 92.3%, and the purity is 99.98%.
Example 19 preparation of milrinone
Intermediate compound I (177.02 g,1.0 mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (152.96 g,1.1 mol) are added into isopropanol (1200 ml), and after being stirred uniformly, sodium isopropoxide is added to adjust the pH value to 12-13; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, regulating the pH value of the solution to 6-7 by hydroiodic acid, stirring to precipitate solids, filtering after the precipitation is finished, pulping a filter cake by using purified water (500 ml) at 40-50 ℃, filtering, and drying to obtain white-like solid milrinone, wherein the yield is 91.4%, and the purity is 99.96%.
Example 20 preparation of milrinone
Intermediate compound I (177.07 g,1.0 mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (236.37 g,1.7 mol) are added into tertiary butanol (1000 ml), and after being stirred uniformly, sodium tertiary butoxide is added to adjust the pH value to 12-13; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding formic acid to adjust the pH value of the solution to 6-7, stirring to precipitate solids, filtering, pulping a filter cake with purified water (500 ml) at 40-50 ℃, filtering, and drying to obtain white-like solid milrinone, wherein the yield is 92.1% and the purity is 99.95%.
Example 21 preparation of milrinone
Intermediate compound I (177.02 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (182.04 g,1.3 mol) are added into ethanol (1200 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 11-12; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 85.8% and the purity is 99.92%.
Example 22 preparation of milrinone
Intermediate compound I (177.06 g,1.0 mol) and alpha- (ethoxymethylene) cyanoacetamide (182.03 g,1.3 mol) are added into ethanol (1200 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 5-6, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 87.5% and the purity is 99.85%.
Example 23 preparation of milrinone
Intermediate compound I (177.06 g,1.0 mol) and alpha- (methoxymethylene) cyanoacetamide (163.84 g,1.3 mol) are added into ethanol (1000 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 92.5% and the purity is 99.90%.
Example 24 preparation of milrinone
Intermediate compound I (177.04 g,1.0 mol) and alpha- (propoxymethylene) cyanoacetamide (200.23 g,1.3 mol) are added into ethanol (1500 ml), and after being stirred evenly, 7.5mol/L sodium hydroxide solution is added to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to regulate the pH value of the solution to 6-7, stirring to precipitate solids, filtering and drying after the precipitation is finished to obtain white-like solid milrinone, wherein the yield is 91.6% and the purity is 99.98%.

Claims (8)

1. A preparation method of milrinone comprises the steps of reacting 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate I, with alpha- (substituted methylene) cyanoacetamide, namely SM-2 to obtain milrinone, wherein the reaction formula is as follows:
Wherein X is one of methoxy, ethoxy, propoxy and dimethylamino; the reaction steps comprise: adding an intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH of the solution, and performing temperature control reaction to obtain milrinone; wherein the alkali is one or a combination of sodium hydroxide, potassium hydroxide, sodium acetate, sodium isopropoxide and sodium tert-butoxide.
2. The method for preparing milrinone according to claim 1, comprising the following steps:
Adding an intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH of the solution, controlling the temperature until the reaction is finished, adding acid to adjust the pH of the solution, precipitating solid, and filtering to obtain milrinone.
3. The method for preparing milrinone according to claim 2, wherein the molar ratio of the intermediate compound I to the α - (substituted methylene) cyanoacetamide is 1:1.1 to 1.7.
4. The method for preparing milrinone according to claim 2, wherein the pH of the solution is adjusted to 12-14 by adding alkali.
5. The method for preparing milrinone according to claim 2, wherein the temperature-controlled reaction temperature is a temperature at which the reaction solution reaches reflux.
6. The method for preparing milrinone according to claim 2, wherein the pH value of the solution is adjusted to 6-7 by adding acid.
7. The method for preparing milrinone according to claim 2, wherein the acid is one or a combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid and hydroiodic acid.
8. The method for preparing milrinone according to claim 2, wherein the reaction solvent is one or two of methanol, ethanol, isopropanol and tert-butanol.
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