CN110590799B - Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate - Google Patents
Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate Download PDFInfo
- Publication number
- CN110590799B CN110590799B CN201910904653.5A CN201910904653A CN110590799B CN 110590799 B CN110590799 B CN 110590799B CN 201910904653 A CN201910904653 A CN 201910904653A CN 110590799 B CN110590799 B CN 110590799B
- Authority
- CN
- China
- Prior art keywords
- isosorbide dinitrate
- acetyl
- preparation
- isosorbide
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention relates to the technical field of medicines, in particular to a preparation method of isomers 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate. Mixing 5-isosorbide dinitrate or 2-isosorbide dinitrate with a catalyst, heating in an oil bath to melt the reactant, stirring and simultaneously adding acetic anhydride or acetic acid after the solid is completely melted, heating until reflux reaction is finished, cooling, extracting, and concentrating an organic layer to obtain the reactant. The synthesis method has reasonable route, strong operability and easy purification of the product, and the obtained target product can be used for qualitatively and quantitatively researching impurities in the detection and analysis of isosorbide mononitrate, so that the quality of isosorbide mononitrate is improved, and the risk of clinical medication is reduced.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of isomers 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate.
Background
Isosorbide 5-mononitrate (5-ISMN), a nitrate-based anti-anginal drug developed in 1981 by bochriger Cnbh, germany. 5-ISMN is an in vivo metabolite of isosorbide dinitrate, has no liver first-pass effect after being taken, has high bioavailability, and has the advantages of quick response, small side effect, high drug effect, long action duration and the like. Isosorbide mononitrate is suitable for long-term treatment of coronary heart disease, prevention of angina pectoris and treatment of continuous angina pectoris after myocardial infarction, is widely applied to clinic since the market of eighties, and is generally popular with patients.
The quality of the medicine is an important standard for measuring the quality of the medicine, and the quality of the medicine is determined by the curative effect and the toxic and side effect of the medicine, namely the effectiveness and the safety of the medicine. It is therefore desirable that the drug be within the therapeutic range without producing severe toxic effects and with little or no side effects. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause non-therapeutic toxic and side effects and must be controlled.
a) 2-O-acetyl-5-isosorbide dinitrate (CAS: 39813-48-4) a synthetic method has been disclosed.
US patent 5614643A, US 5538891A and european patent EP 0530671B 1 disclose a method for synthesizing 2-O-acetyl-5-isosorbide dinitrate, which comprises the following steps: 6.91g (30 mmol) of isosorbide 2, 5-acetate is dissolved in 15ml of THF, added to 60ml of phosphate buffer, and then 500mg of lipase from Pseudomonas fluorescens is added under the condition of pH7.0, and 1mol/L of sodium hydroxide is added continuously by an automatic titrator to keep the pH of the solution stable. After 24h, about 29.07ml of 1mol/L sodium hydroxide solution is consumed, ethyl acetate is added for extraction after the reaction is finished, the organic phase is dried by anhydrous magnesium sulfate, the solvent is removed by evaporation, and the crude product is separated by a silica gel chromatographic column. 5.00g of isosorbide 2-acetate was obtained in 89% yield. 1.4 ml of 65% nitric acid are mixed with 5.5 ml of acetic anhydride at 0 ℃ and at this temperature 1.4 ml of dichloromethane and 2.6 g (13.8 mmol) of isosorbide 2-acetate solution are added dropwise. After stirring at room temperature for another 20 minutes, 2.8 ml of methylene chloride and 6.9 ml of water were added to separate the layers. Neutralizing the organic phase with diluted ammonia water, and MgSO4Drying and evaporating the solvent. 2-O-acetyl-5-isosorbide dinitrate is obtained with a yield of 85%. The disadvantages of this method are: the 2-isosorbide acetate is prepared by adopting lipase selective reduction, and then the 5 th site is nitrified, so that the reaction steps are more, the reaction time is longer, the reaction conditions are harsh, and the purity cannot be guaranteed.
European patent WO2018/172496 a discloses a method for synthesizing 2-O-acetyl-5-isosorbide dinitrate, which comprises the following steps: isosorbide mononitrate 1.91 g (10mmol) was dissolved in 50ml dichloromethane and triethylamine 1.52 ml (11mmol), 4-dimethylaminopyridine 0.244 g (2mmol) were added followed by acetic anhydride (11 mmol). The reaction mixture was stirred for 3 hours. The reaction was monitored by thin layer chromatography (1:1 n-hexane: ethyl acetate) to observe the disappearance of ISMN. Once complete, the mixture was washed with 50ml of 1M HCI, 50ml of saturated sodium bicarbonate solution, 50ml of saturated aqueous salt solution and the organic layer was dried over 1g of anhydrous sodium sulfate. The methylene chloride was evaporated to dryness and purified with diethyl ether to obtain 2.133 g of a white powder with a yield of 91.54%. The disadvantages of this method are: although the route is short, organic solvents such as triethylamine, 4-dimethylaminopyridine and the like are used, the environment is polluted, and a large amount of acid-containing and alkali-containing wastewater is generated by acid washing and alkali washing in the post-treatment process, so that the environment is polluted.
b) 5-O-acetyl-2-isosorbide dinitrate (CAS:39698-15-2) a synthetic method has been disclosed.
Meanwhile, the above patent also discloses a preparation method of 5-O-acetyl-2-isosorbide dinitrate, which comprises the following steps:
1.46g (10mmol) of isosorbide are dissolved in 20ml of acetone, 2.77ml (30 mmol) of acetic anhydride and 200mg of lipase from Pseudomonas fluorescens are stirred at room temperature, after 3 days of reaction, the lipase is filtered off, the acetone is washed, the solvent is evaporated to dryness and the crude product is concentrated in a bulb tube. Isosorbide 5-acetate 1.70g was obtained in 90% yield.
0.2ml of 65% nitric acid is mixed with 0.8 ml of acetic anhydride at 0 ℃ and a solution of 330 mg (1.75 mmol) of 5-isosorbide acetate in 0.2ml of dichloromethane is added dropwise at this temperature. After stirring at room temperature for 20 minutes, 0.4ml of methylene chloride and 1ml of water were added to separate the layers. Neutralizing organic phase with diluted ammonia water, and anhydrous MgSO4Drying and evaporating the solvent. 5-O-acetyl-2-isosorbide dinitrate is obtained with a yield of 98%.
According to the method, isosorbide 5-acetate nitrate is synthesized firstly, then the 2 nd site is nitrified, so that the method has the advantages of more reaction raw materials, long reaction time, complex process and low product purity.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method of isomer 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate.
The purpose of the invention is realized as follows:
a method for preparing 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate, said 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate being isomers, comprising the steps of:
the preparation method of the 2-O-acetyl-5-isosorbide dinitrate comprises the following steps: mixing 5-isosorbide dinitrate and a catalyst, heating the mixture in an oil bath to 100 ℃ to melt reactants, stirring and simultaneously adding acetic anhydride or acetic acid after the solid is completely melted, heating the mixture until reflux reaction is finished, cooling, extracting, drying an organic layer, dissolving an organic solvent, decoloring, performing heat filtration, concentrating, standing and crystallizing;
reaction scheme 1
The preparation method of the 5-O-acetyl-2-isosorbide dinitrate comprises the following steps: mixing 2-isosorbide dinitrate with a catalyst, heating the mixture in an oil bath to 105 ℃ to melt the reactant, stirring and simultaneously adding acetic anhydride or acetic acid after the solid is completely melted, heating the mixture to reflux reaction, cooling the reaction liquid to room temperature after the reflux reaction is finished, extracting, concentrating an organic layer, recrystallizing the concentrate, and airing to obtain a white solid which is 5-O-acetyl-2-isosorbide dinitrate.
Reaction formula 2
Preferably, the reflux reaction time in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate is 0.5-3 h, and more preferably 1 h.
Preferably, the molar ratio of the 5-isosorbide-nitrate or the 2-isosorbide nitrate to the acetic anhydride or the acetic acid in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate is 1: 1-5, and more preferably 1: 1.2.
Preferably, the catalyst in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate is sodium acetate.
Preferably, the molar ratio of the 5-isosorbide dinitrate or the 2-isosorbide dinitrate to the catalyst in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate is 1: 0.02-0.10, and more preferably 1: 0.025.
Preferably, the extraction solvent used in the step of the preparation method of 2-O-acetyl-5-isosorbide dinitrate or 5-O-acetyl-2-isosorbide dinitrate is one of ethyl acetate, chloroform and dichloromethane, and more preferably ethyl acetate.
Preferably, the melting temperature is increased to 70-120 ℃ in the preparation method step of the 2-O-acetyl-5-isosorbide dinitrate or 5-O-acetyl-2-isosorbide dinitrate.
Preferably, in the preparation method of 2-O-acetyl-5-isosorbide dinitrate, the specific reaction after the reflux is finished is as follows: cooling the reaction liquid to room temperature, adding ethyl acetate, separating liquid, washing an organic layer with saturated salt water, washing with water, separating liquid, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, dissolving with chloroform, decoloring with activated carbon, performing heat filtration, concentrating, standing and crystallizing.
Preferably, the specific reaction after the reflux in the preparation method of 5-O-acetyl-2-isosorbide dinitrate is as follows: cooling the reaction liquid to room temperature, adding chloroform, stirring for dissolving, washing, separating liquid, concentrating the chloroform under reduced pressure, recrystallizing the concentrate with ethanol, and airing at room temperature to obtain a white solid which is 5-O-acetyl-2-isosorbide dinitrate.
Advantageous effects
(1) The invention provides a preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate impurities, which is simple and feasible, has few used raw materials, is more environment-friendly, has few impurities and has good purity.
(2) The synthetic route provided by the invention is simple and the reaction condition is mild.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Example 1
Weighing 19.11g (0.1 mol) of 5-isosorbide mononitrate, adding the weighed mass into a 250ml three-necked bottle, then weighing 0.26g (0.003 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 105 ℃, melting the reactant, adding 12.44g (0.12 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction for 1.5h, cooling the reaction solution to 0-5 ℃ in an ice water bath, precipitating a large amount of solid, and performing suction filtration to obtain 13.43g of wet product of the crude product of the 2-O-acetyl-5-isosorbide mononitrate.
Refining: adding the crude product into 19.56g chloroform, heating for dissolving, cooling in 0 deg.C ice ethanol bath, and crystallizing for 30 min. And (3) filtering, and airing at room temperature to obtain 8.06g of 2-O-acetyl-5-isosorbide dinitrate refined product, wherein the molar yield is 34.06%, and related substances are detected by 99.18%.
Example 2
Weighing 100.00g (0.52 mol) of 5-isosorbide mononitrate, adding the weighed 5-isosorbide mononitrate into a 250ml three-necked bottle, then weighing 1.04g (0.013 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 100 ℃, melting the reactant, adding 64.00g (0.63 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction, carrying out reflux reaction for 1h, cooling the mixture to room temperature, transferring the reaction solution into a 500ml three-necked bottle, adding 200ml of ethyl acetate and 200ml of saturated salt water, stirring the mixture for 15min, standing the mixture for layering, adding 300ml of ethyl acetate into the water phase, extracting the mixture once, combining the ethyl acetate, adding 400ml of purified water, washing the mixture once, separating the liquid, and separating the ethyl acetate. 150g of anhydrous sodium sulfate was added and dried overnight. And (3) carrying out suction filtration, evaporating the filtrate under reduced pressure to remove ethyl acetate, adding 90g of chloroform into the concentrate, heating to dissolve, carrying out crystallization on the solution in ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain 67.89g of crude wet weight.
Refining: transferring the crude product into a 250ml three-necked bottle, adding 90g of chloroform, heating to reflux, adding 5g of activated carbon, carrying out hot filtration, concentrating the filtrate to dryness, adding 30g of chloroform, heating to reflux and dissolve, standing at room temperature for crystallization, carrying out crystallization on the filtrate in an ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain a refined product of the 2-O-acetyl-5-isosorbide dinitrate, wherein the molar yield is 41.43g, and the related substances are detected to be 99.76%.
Example 3
Weighing 17.0g (0.09 mol) of isosorbide 2-mononitrate, adding the isosorbide 2-mononitrate into a 250ml three-necked bottle, then weighing 0.18g (0.002 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 105 ℃, melting the reactant, adding 10.77g (0.11 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction for 1 hour, cooling the reaction solution to room temperature, adding 30ml of chloroform, stirring and dissolving, washing the solution for 5 times by using 30ml of purified water, evaporating the chloroform under reduced pressure, adding 10ml of absolute ethyl alcohol for dissolving, cooling the solution by using an ice-ethanol bath at the temperature of-5 ℃ for crystallization for 1 hour, separating out the solid, and performing suction filtration to obtain 14g of a crude product of 5-O-acetyl-2-isosorbide dinitrate, wherein the molar yield is 67.5%, and related substances are detected to be 95.48%.
Refining: adding 14g (weight after air drying) of the crude product into 10ml of absolute ethyl alcohol, heating for dissolving, cooling and crystallizing in an ice-ethanol bath at 0 ℃. And (3) filtering, and airing at room temperature to obtain 6.62g of 2-O-acetyl-5-isosorbide dinitrate refined product, wherein the molar yield is 31.9%, and the purity is 98.80% according to the detection result of related substances.
Example 4
Weighing 17.0g (0.09 mol) of isosorbide 2-mononitrate, adding the isosorbide 2-mononitrate into a 250ml three-necked bottle, then weighing 0.18g (0.002 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 105 ℃, melting the reactant, adding 45.94g (0.45 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction for 1 hour, cooling the reaction solution to room temperature, adding 30ml of chloroform, stirring and dissolving, washing with 30ml of purified water for 5 times, evaporating the chloroform under reduced pressure, adding 10ml of absolute ethyl alcohol for dissolving, cooling and crystallizing for 1 hour by an ice-ethanol bath at the temperature of-5 ℃, separating out the solid, and performing suction filtration to obtain 12g of a crude product of isosorbide 5-O-acetyl-2-nitrate, wherein the molar yield is 57.9%, and related substances are detected to be 94.80%.
Example 5
Weighing 17.0g (0.09 mol) of 2-isosorbide mononitrate, adding the weighed 2-isosorbide mononitrate into a 250ml three-necked bottle, then weighing 0.18g (0.002 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 105 ℃, melting the reactant, adding 9.19g (0.09 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction for 1 hour, cooling the reaction solution to room temperature, adding 30ml of chloroform, stirring and dissolving, washing the solution for 5 times by using 30ml of purified water, evaporating the chloroform under reduced pressure, adding 10ml of absolute ethyl alcohol for dissolving, cooling and crystallizing the solution for 1 hour by using an ice-ethanol bath at the temperature of-5 ℃, separating out the solid, and performing suction filtration to obtain 13g of a crude product of the 5-O-acetyl-2-isosorbide mononitrate, wherein the molar yield is 62.7%, and related substances are detected by 94.93%.
Example 6
Weighing 100.00g (0.52 mol) of 5-isosorbide mononitrate, adding the weighed 5-isosorbide mononitrate into a 250ml three-necked bottle, then weighing 4.16g (0.052 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 100 ℃, melting the reactant, adding 64.00g (0.63 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction, carrying out reflux reaction for 1h, cooling the mixture to room temperature, transferring the reaction solution into a 500ml three-necked bottle, adding 200ml of ethyl acetate and 200ml of saturated saline, stirring the mixture for 15min, standing the mixture for layering, adding 300ml of ethyl acetate into the water phase, extracting the mixture once, combining the ethyl acetate, adding 400ml of purified water, washing the mixture once, separating the liquid and separating the ethyl acetate. 150g of anhydrous sodium sulfate was added and dried overnight. And (3) carrying out suction filtration, evaporating the filtrate under reduced pressure to remove ethyl acetate, adding 90g of chloroform into the concentrate, heating to dissolve, carrying out crystallization on the solution in ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain a crude product with the wet weight of 60.01 g.
Refining: transferring the crude product into a 250ml three-necked bottle, adding 90g of chloroform, heating to reflux, adding 5g of activated carbon, carrying out hot filtration, concentrating the filtrate to dryness, adding 30g of chloroform, heating to reflux and dissolve, standing at room temperature for crystallization, carrying out crystallization on the filtrate in an ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain a 2-O-acetyl-5-isosorbide nitrate refined product with the weight of 36.6g, the molar yield of 30.1 percent and related substances of 97.85 percent.
Example 7
Weighing 100.00g (0.52 mol) of 5-isosorbide mononitrate, adding the weighed 5-isosorbide mononitrate into a 250ml three-necked bottle, then weighing 0.85g (0.0104 mol) of sodium acetate, adding the sodium acetate into the reaction bottle, heating the oil bath to 100 ℃, melting the reactant, adding 64.00g (0.63 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction, carrying out reflux reaction for 1h, cooling the mixture to room temperature, transferring the reaction solution into a 500ml three-necked bottle, adding 200ml of ethyl acetate and 200ml of saturated saline, stirring the mixture for 15min, standing the mixture for layering, adding 300ml of ethyl acetate into the water phase, extracting the mixture once, combining the ethyl acetate, adding 400ml of purified water, washing the mixture once, separating the liquid and separating the ethyl acetate. 150g of anhydrous sodium sulfate was added and dried overnight. And (3) carrying out suction filtration, evaporating the filtrate under reduced pressure to remove ethyl acetate, adding 90g of chloroform into the concentrate, heating to dissolve, carrying out crystallization on the solution in ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain a crude product with the wet weight of 60.01 g.
Refining: transferring the crude product into a 250ml three-necked bottle, adding 90g of chloroform, heating to reflux, adding 5g of activated carbon, carrying out hot filtration, concentrating the filtrate to dryness, adding 30g of chloroform, heating to reflux for dissolution, standing at room temperature for crystallization, carrying out crystallization on the filtrate in an ice water bath at the temperature of-5 ℃, and carrying out suction filtration to obtain a 2-O-acetyl-5-isosorbide nitrate refined product with the weight of 35.9g, the molar yield of 29.5 percent and related substances of 97.66 percent.
Comparative example 1
Weighing 19.11g (0.1 mol) of 5-isosorbide mononitrate, adding the weighed mass into a 250ml three-necked bottle, then weighing 0.36g (0.003 mol) of 4-N, N-dimethylaminopyridine, adding the weighed mass into the reaction bottle, heating the oil bath to 105 ℃, melting the reactant, adding 12.44g (0.12 mol) of acetic anhydride after the solid is completely dissolved, heating the mixture to reflux reaction, carrying out the reflux reaction for 1.5h, cooling the reaction solution to 0-5 ℃ in ice water bath, precipitating the solid, and carrying out suction filtration to obtain 10.36g of wet product of the crude 2-O-acetyl-5-isosorbide mononitrate.
Refining: adding the crude product into 19.56g chloroform, heating for dissolving, cooling in 0 deg.C ice ethanol bath, and crystallizing for 30 min. And (3) filtering, and airing at room temperature to obtain 6.85g of 2-O-acetyl-5-isosorbide dinitrate refined product, wherein the molar yield is 28.95%, and related substances are detected by 90.18%.
Claims (6)
- A method for preparing 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate, said 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate being isomers, characterized in that it comprises the following steps:the preparation method of the 2-O-acetyl-5-isosorbide dinitrate comprises the following steps: mixing 5-isosorbide dinitrate and a catalyst, heating the mixture in an oil bath to 100 ℃ to melt reactants, stirring and simultaneously adding acetic anhydride or acetic acid after the solid is completely melted, heating the mixture until reflux reaction is finished, cooling, extracting, drying an organic layer, dissolving an organic solvent, decoloring, performing heat filtration, concentrating, standing and crystallizing;the preparation method of the 5-O-acetyl-2-isosorbide dinitrate comprises the following steps: mixing 2-isosorbide dinitrate and a catalyst, heating the mixture in an oil bath to 105 ℃ to melt a reactant, stirring the mixture while adding acetic anhydride or acetic acid after the solid is completely melted, heating the mixture to reflux reaction, cooling the reaction solution to room temperature after the reflux reaction is finished, extracting, concentrating an organic layer, recrystallizing the concentrate, and airing the concentrate to obtain a white solid;in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate, the molar ratio of 5-isosorbide dinitrate or 2-isosorbide dinitrate to acetic anhydride or acetic acid is 1: 1-5;the catalyst in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate or the 5-O-acetyl-2-isosorbide dinitrate is sodium acetate;in the preparation method of the 2-O-acetyl-5-isosorbide dinitrate and the 5-O-acetyl-2-isosorbide dinitrate, the molar ratio of the 5-isosorbide dinitrate or the 2-isosorbide dinitrate to the catalyst is 1: 0.02-0.10.
- 2. The method according to claim 1, wherein the reflux reaction time is 0.5 to 3 hours for each of the 2-O-acetyl-5-isosorbide dinitrate and the 5-O-acetyl-2-isosorbide dinitrate.
- 3. The method according to claim 1, wherein the extraction solvent used in the step of the method for producing 2-O-acetyl-5-isosorbide dinitrate or 5-O-acetyl-2-isosorbide dinitrate is one of ethyl acetate, chloroform and dichloromethane.
- 4. The preparation method according to claim 1, wherein the temperature rise melting temperature in the step of the preparation method of 2-O-acetyl-5-isosorbide dinitrate or 5-O-acetyl-2-isosorbide dinitrate is 70-120 ℃.
- 5. The preparation method according to claim 1, wherein the specific reaction after the end of reflux in the preparation method of 2-O-acetyl-5-isosorbide dinitrate is: cooling the reaction liquid to room temperature, adding ethyl acetate, separating liquid, washing an organic layer with saturated salt water, washing with water, separating liquid, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, dissolving with chloroform, decoloring with activated carbon, performing heat filtration, concentrating, standing and crystallizing.
- 6. The preparation method according to claim 1, wherein the specific reaction after the end of reflux in the preparation method of 5-O-acetyl-2-isosorbide dinitrate is: cooling the reaction liquid to room temperature, adding chloroform, stirring for dissolving, washing, separating liquid, concentrating the chloroform under reduced pressure, recrystallizing the concentrate with ethanol, and airing at room temperature to obtain a white solid which is 5-O-acetyl-2-isosorbide dinitrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910904653.5A CN110590799B (en) | 2019-09-24 | 2019-09-24 | Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910904653.5A CN110590799B (en) | 2019-09-24 | 2019-09-24 | Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110590799A CN110590799A (en) | 2019-12-20 |
| CN110590799B true CN110590799B (en) | 2022-04-22 |
Family
ID=68862822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910904653.5A Active CN110590799B (en) | 2019-09-24 | 2019-09-24 | Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110590799B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456187A (en) * | 2020-11-09 | 2022-05-10 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate rod-shaped crystal and preparation method thereof |
| CN117143537A (en) * | 2023-09-13 | 2023-12-01 | 深圳市捷易联电子有限公司 | Pressure-sensitive adhesive tape for lithium battery packaging and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0530671A2 (en) * | 1991-09-02 | 1993-03-10 | Roche Diagnostics GmbH | Process for the enzymatic preparation of pure isosorbide-2 or 5-monoester-isomers and conversion to isosorbide-2- and 5-nitrate |
| CN103130815A (en) * | 2013-02-07 | 2013-06-05 | 浙江工业大学 | Isosorbide mononitrate derivative and preparation method and application thereof |
| WO2018172496A1 (en) * | 2017-03-24 | 2018-09-27 | Solvotrin Therapeutics Ltd | Compounds and compositions for use in treating psoriasis |
-
2019
- 2019-09-24 CN CN201910904653.5A patent/CN110590799B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0530671A2 (en) * | 1991-09-02 | 1993-03-10 | Roche Diagnostics GmbH | Process for the enzymatic preparation of pure isosorbide-2 or 5-monoester-isomers and conversion to isosorbide-2- and 5-nitrate |
| CN103130815A (en) * | 2013-02-07 | 2013-06-05 | 浙江工业大学 | Isosorbide mononitrate derivative and preparation method and application thereof |
| WO2018172496A1 (en) * | 2017-03-24 | 2018-09-27 | Solvotrin Therapeutics Ltd | Compounds and compositions for use in treating psoriasis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110590799A (en) | 2019-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8367847B2 (en) | Production of monatin enantiomers | |
| CN110590799B (en) | Preparation method of 2-O-acetyl-5-isosorbide dinitrate and 5-O-acetyl-2-isosorbide dinitrate | |
| JP2000109497A (en) | Spiro ring type c-glycoside | |
| JP5799171B2 (en) | Method for producing 1-palmitoyl-3-acetylglycerol and method for producing 1-palmitoyl-2-linoleoyl-3-acetylglycerol using the same | |
| WO2008092405A1 (en) | Method for synthesizing 1,2,3-tri-o-acetyl-5-deoxy-d-ribose | |
| JP2012136544A (en) | Process for producing docetaxel, and medicine | |
| CN107849043A (en) | For preparing the method for the formamide of 1,6 naphthyridines of (4S) 4 (methoxyphenyl of 4 cyano group 2) 5 ethyoxyl, 2,8 dimethyl, 1,4 dihydro 3 and its for the purifying as pharmaceutically active substance | |
| KR20120111929A (en) | Process for producing pyripyropene derivative | |
| KR20130040180A (en) | Process for producing pyripyropene derivatives | |
| CN105622538B (en) | One kettle way prepares Cetilistat in high yield | |
| DE60014374T2 (en) | TAXAN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF | |
| CN114380877B (en) | Preparation method of 2' -deoxy-2 ' -beta-fluoro-4 ' -azidocytidine | |
| CN107011354B (en) | Preparation method of 5-isosorbide mononitrate | |
| JP5460209B2 (en) | Method for purifying 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide | |
| JP7244487B2 (en) | Crystalline or amorphous steroidal derivative FXR agonist, its preparation method and use | |
| KR20070053697A (en) | Improved process for the manufacture of mirtazapine | |
| RU2658838C1 (en) | Method for producing allobetulin succinate | |
| CN110407846B (en) | Preparation method of 5-isosorbide mononitrate | |
| JPH03209393A (en) | Synthesis of 1-(3-azide-2, 3-dideoxy-beta- d-erythropentfuranosil) thymine and its related compound | |
| CN115175913A (en) | Substituted bistricyclic compounds, pharmaceutical compositions and uses thereof | |
| CN108409561B (en) | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate | |
| JPH0696572B2 (en) | Pyridonecarboxylic acid derivatives, their esters and their salts | |
| JP4014329B2 (en) | Purification method of quinoline derivatives | |
| CN111574520A (en) | Riagliptin intermediate compound V | |
| US20240124482A1 (en) | New compounds and methods of their manufacturing |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |