CN111484450A - Preparation method of medical intermediate milrinone - Google Patents
Preparation method of medical intermediate milrinone Download PDFInfo
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- CN111484450A CN111484450A CN201910081492.4A CN201910081492A CN111484450A CN 111484450 A CN111484450 A CN 111484450A CN 201910081492 A CN201910081492 A CN 201910081492A CN 111484450 A CN111484450 A CN 111484450A
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- milrinone
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- acetic anhydride
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- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960003574 milrinone Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 60
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000003756 stirring Methods 0.000 claims abstract description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001816 cooling Methods 0.000 claims abstract description 22
- ILRVKOYYFFNXDB-UHFFFAOYSA-N 1-pyridin-4-ylpropan-2-one Chemical compound CC(=O)CC1=CC=NC=C1 ILRVKOYYFFNXDB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000010992 reflux Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000000706 filtrate Substances 0.000 claims abstract description 14
- 229960000583 acetic acid Drugs 0.000 claims abstract description 13
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 8
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000004927 clay Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000012267 brine Substances 0.000 claims description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 12
- 238000005292 vacuum distillation Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- UEBDZDZLEVYUEC-UHFFFAOYSA-N caerulomycinonitrile Chemical compound COC1=CC(C#N)=NC(C=2N=CC=CC=2)=C1 UEBDZDZLEVYUEC-UHFFFAOYSA-N 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940124975 inotropic drug Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of a medical intermediate milrinone, which comprises the steps of S1, adding 4-methylpyridine and acetic anhydride into a reaction bottle in sequence, dropwise adding concentrated sulfuric acid, stirring for reacting for 20-30 minutes, continuing to react at 40-60 ℃, reacting completely at T L C, cooling in an ice bath, dropwise adding ethanol, stirring for 1 hour, heating and refluxing for 6-8 hours, extracting with dichloromethane, drying, filtering, removing dichloromethane by rotary evaporation of filtrate, distilling under reduced pressure to evaporate 4-methylpyridine, cooling, distilling under reduced pressure to obtain 1- (4-pyridyl) -acetone, S2, mixing 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride, adding α -cyanoacetamide to cyclize under an alkaline condition to obtain a milrinone crude product, S3, adding DMF into the milrinone crude product obtained in S2, stirring until a solid is dissolved, adding a decolorizing agent, stirring, refluxing for 8-20 minutes, filtering, cooling and separating out the filtrate to obtain the refined milrinone crude product.
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of a medical intermediate milrinone.
Background
Milrinone, chemical name is 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine ] -5-carbonitrile, molecular formula is C12H9N3O, molecular weight is 211.22, and it is white or white-like crystalline powder.
Milrinone is a positive inotropic drug of non-digitalis cardiac glycoside and non-catecholamine, can inhibit phosphodiesterase of heart to produce positive contraction and peripheral vasodilatation, and is suitable for treating patients with severe congestive heart failure.
The existing milrinone preparation method generally has the defects of complex synthesis line, higher equipment requirement, expensive and difficultly-obtained raw materials, poor product quality and the like. In addition, the milrinone produced by the prior art has darker color, can meet the requirements of raw material medicaments for injection only by repeated refining and decoloring, and has high cost; forced decolorization can increase impurities and reduce purity.
Disclosure of Invention
The invention aims to overcome the defects and provides a preparation method of a medical intermediate milrinone, which is simple and safe, is convenient for realizing industrial production and has the product purity of more than 99.5 percent.
In order to achieve the purpose, the invention provides the following technical scheme that the preparation method of the medical intermediate milrinone comprises the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring and reacting at 20-30 ℃ for 20-30 minutes, continuously reacting at 40-60 ℃, completely reacting at T L C, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuously stirring for 1 hour after dropwise adding, heating and refluxing for 6-8 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by using a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by using an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 55-95 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 8-20 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
Further, in the step S1, the molar ratio of the 4-methylpyridine to the acetic anhydride is 1: 1-2.5.
Further, in the step S1, dichloromethane is used for extraction 3 times.
Further, in the step S2, the molar ratio of the 1- (4-pyridyl) -acetone to the triethyl orthoformate to the glacial acetic acid to the acetic anhydride is 1: 0.8-1.5: 12-20: 22-30.
Further, the decoloring agent in the step S3 is a mixture of activated clay and silica gel.
By adopting the technical scheme, the activated carbon is used as a decoloring agent in the prior art, the decoloring effect of activated clay is superior to that of silica gel, the silica gel and the activated clay are mixed and used as the decoloring agent, and the silica gel can prevent the activated clay from blocking filter holes in the filtering process and reduce the loss of products in the filtering process.
Further, the decoloring agent is composed of the following raw materials in percentage by mass: 60 to 80 percent of activated clay and 20 to 40 percent of silica gel.
Preferably, the stirring and refluxing in the step S3 are performed for 10 minutes.
Further, the mass volume of the milrinone crude product and DMF in the step S3 is 1g: 2-5 m L.
By adopting the technical scheme, the solubility of the milrinone in DMF at room temperature of 30 ℃ is less than 0.1g/10m L DMF, but the solubility of the milrinone can reach 4g/10m L DMF when the DMF flows back.
Further, in step S1, the ice bath is used for cooling.
Further, the water pump reduced pressure distillation in the step S1 is performed at a vacuum degree of 800mmHg and a temperature of 65-73 ℃, and the oil pump reduced pressure distillation in the step S2 is performed at a vacuum degree of 20mmHg and a temperature of 130-135 ℃.
Compared with the prior art, the invention has the beneficial effects that:
1. in the step S1 of the preparation method of the medical intermediate milrinone, 4-methylpyridine and acetic anhydride are used as raw materials to prepare the 1- (4-pyridyl) -acetone, wherein the distilled raw material 4-methylpyridine can be recycled, so that the raw material cost is saved.
2. The milrinone prepared by the preparation method of the medical intermediate milrinone has the purity of more than 99.5 percent, and the product is white solid in appearance, thereby meeting the requirements of raw material medicines for injection.
3. The preparation method of the medical intermediate milrinone is simple and safe, is convenient for realizing industrial production, saves the cost of raw materials, and improves the purity, yield and color degree of products.
Drawings
FIG. 1 is a flow chart of the preparation process of the present invention.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Example 1
A preparation method of a medical intermediate milrinone comprises the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring at 28 ℃ for reaction for 30 minutes, continuing to react at 42 ℃, completely reacting T L C, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuing to stir for 1 hour after the dropwise adding, heating and refluxing for 6 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 60 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 10 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
Wherein the molar ratio of 4-methylpyridine to acetic anhydride in step S1 is 1:2.
In step S1, 200m L of dichloromethane was used for extraction 3 times.
Wherein the molar ratio of 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride in the step S2 is 1:1:20: 29.
Wherein, the decolorizing agent in the step S3 comprises the following raw materials in percentage by mass: 80% of activated clay and 20% of silica gel.
In step S3, the mixture was refluxed with stirring for 10 minutes.
Wherein the mass volume of the milrinone crude product and the DMF in the step S3 is 1g:2m L.
In step S1, the mixture was cooled in an ice bath using brine ice.
Wherein, the water pump vacuum distillation in step S1 is performed at a vacuum degree of 800mmHg and a temperature of 73 ℃, and the oil pump vacuum distillation in step S2 is performed at a vacuum degree of 20mmHg and a temperature of 135 ℃.
Example 2
A preparation method of a medical intermediate milrinone comprises the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring at 30 ℃ for reacting for 25 minutes, continuously reacting at 60 ℃, completely reacting T L C, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuously stirring for 1 hour after dropwise adding, heating and refluxing for 7 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by using a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by using an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 90 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 15 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
Wherein, the molar ratio of the 4-methylpyridine to the acetic anhydride in the step S1 is 1: 1.5.
In step S1, 200m L of dichloromethane was used for extraction 3 times.
Wherein the molar ratio of 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride in the step S2 is 1:1.2:13: 25.
Wherein, the decolorizing agent in the step S3 comprises the following raw materials in percentage by mass: 60% of activated clay and 40% of silica gel.
In step S3, the mixture was refluxed with stirring for 10 minutes.
Wherein the mass volume of the milrinone crude product and the DMF in the step S3 is 1g:3m L.
In step S1, the mixture was cooled in an ice bath using brine ice.
Wherein, the water pump reduced pressure distillation in the step S1 is performed under the vacuum degree of 800mmHg and the temperature of 65-73 ℃, and the oil pump reduced pressure distillation in the step S2 is performed under the vacuum degree of 20mmHg and the temperature of 130-135 ℃.
Example 3
A preparation method of a medical intermediate milrinone comprises the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring at 28 ℃ for reaction for 26 minutes, continuing to react at 30 ℃, completely reacting T L C, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuing to stir for 1 hour after the dropwise adding, heating and refluxing for 8 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by using a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by using an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 90 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 20 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
Wherein, the molar ratio of the 4-methylpyridine to the acetic anhydride in the step S1 is 1: 2.5.
In step S1, 200m L of dichloromethane was used for extraction 3 times.
Wherein the molar ratio of 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride in the step S2 is 1:1:20: 22.
Wherein, the decolorizing agent in the step S3 comprises the following raw materials in percentage by mass: 60 to 80 percent of activated clay and 20 to 40 percent of silica gel.
In step S3, the mixture was refluxed with stirring for 10 minutes.
Wherein the mass volume of the milrinone crude product and the DMF in the step S3 is 1g:4m L.
In step S1, the mixture was cooled in an ice bath using brine ice.
Wherein, the water pump vacuum distillation in step S1 is performed at a vacuum degree of 800mmHg and a temperature of 73 ℃, and the oil pump vacuum distillation in step S2 is performed at a vacuum degree of 20mmHg and a temperature of 130 ℃.
Example 4
A preparation method of a medical intermediate milrinone comprises the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring at 28 ℃ for reacting for 20 minutes, continuously reacting at 40 ℃, completely reacting at T L ℃, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuously stirring for 1 hour after dropwise adding, heating and refluxing for 8 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by using a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by using an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 90 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 16 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
Wherein the molar ratio of 4-methylpyridine to acetic anhydride in step S1 is 1:2.
In step S1, the extraction was performed 3 times using methylene chloride.
Wherein the molar ratio of 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride in the step S2 is 1:00.9:15: 26.
Wherein, the decolorizing agent in the step S3 comprises the following raw materials in percentage by mass: 75% of activated clay and 25% of silica gel.
In step S3, the mixture was refluxed with stirring for 10 minutes.
Wherein the mass volume of the milrinone crude product and the DMF in the step S3 is 1g:2m L.
In step S1, the mixture was cooled in an ice bath using brine ice.
Wherein the water pump vacuum distillation in step S1 is performed at a vacuum degree of 800mmHg and a temperature of 70 deg.C, and the oil pump vacuum distillation in step S2 is performed at a vacuum degree of 20mmHg and a temperature of 132 deg.C.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A preparation method of a medical intermediate milrinone is characterized by comprising the following steps:
s1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, slowly dropwise adding concentrated sulfuric acid, stirring and reacting at 20-30 ℃ for 20-30 minutes, continuously reacting at 40-60 ℃, completely reacting at T L C, cooling to below 10 ℃ in an ice bath, slowly dropwise adding ethanol, continuously stirring for 1 hour after dropwise adding, heating and refluxing for 6-8 hours, extracting with dichloromethane after the reaction is finished, drying, filtering, rotationally evaporating the obtained filtrate to remove dichloromethane serving as a solvent, distilling by using a water pump under reduced pressure to evaporate 4-methylpyridine, cooling, and distilling by using an oil pump under reduced pressure to obtain 1- (4-pyridyl) -acetone;
s2, mixing the 1- (4-pyridyl) -acetone obtained in the step S1, triethyl orthoformate, glacial acetic acid and acetic anhydride, reacting at 55-95 ℃, adding ethanol into the reactant, adding α -cyanoacetamide, and cyclizing under an alkaline condition to obtain a milrinone crude product;
s3, adding DMF into the milrinone crude product obtained in the step S2, heating and stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 8-20 minutes, filtering, and cooling the filtrate to separate out refined milrinone.
2. The method of claim 1, wherein the molar ratio of 4-methylpyridine to acetic anhydride in the step S1 is 1: 1-2.5.
3. The method of claim 1, wherein the extraction in step S1 is performed 3 times using dichloromethane.
4. The method of claim 1, wherein the molar ratio of 1- (4-pyridyl) -acetone, triethyl orthoformate, glacial acetic acid, and acetic anhydride in step S2 is 1: 0.8-1.5: 12-20: 22-30.
5. The method of claim 1, wherein the decolorizing agent of step S3 is a mixture of activated clay and silica gel.
6. The method for preparing milrinone as a medical intermediate of claim 1, wherein the decolorizing agent comprises the following raw materials by mass percent: 60 to 80 percent of activated clay and 20 to 40 percent of silica gel.
7. The method of claim 1, wherein the step S3 is performed by stirring and refluxing for 10 min.
8. The method for preparing the medical intermediate milrinone of claim 1, wherein the mass volume of the milrinone crude product and DMF in step S3 is 1g: 2-5 m L.
9. The method of claim 1, wherein the step S1 is performed by using an ice bath of brine ice.
10. The method of claim 1, wherein the step S1 is performed under vacuum of 800mmHg at 65-73 ℃, and the step S2 is performed under vacuum of 20mmHg at 130-135 ℃.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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