CN102603760A - Synthesis method of anti-angina drug isosorbide mononitrate - Google Patents
Synthesis method of anti-angina drug isosorbide mononitrate Download PDFInfo
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- CN102603760A CN102603760A CN2011100258838A CN201110025883A CN102603760A CN 102603760 A CN102603760 A CN 102603760A CN 2011100258838 A CN2011100258838 A CN 2011100258838A CN 201110025883 A CN201110025883 A CN 201110025883A CN 102603760 A CN102603760 A CN 102603760A
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- isosorbide mononitrate
- isosorbide
- ismo
- angina drug
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Abstract
The invention relates to a synthesis method of anti-angina drug isosorbide mononitrate, which comprises the following steps: using sorbitol as a raw material, purifying dehydrated mixture by active carbon filtration after finishing dehydration reaction; directly nitrifying or indirectly nitrifying obtained isosorbitol to obtain the anti-angina drug isosorbide mononitrate. The invented synthesis method has the following advantages: the synthesis process avoids using high energy consuming operation such as high vacuum and high temperature, and greatly simplifies the synthesis process condition, runs equipment conveniently and safely and obviously reduces the production cost. The invented synthesis method is suitable for industrial production and is expected to realize energy conservation and emission reduction reform of prior 5-isosorbide mononitrate production equipment.
Description
[technical field]
The present invention relates to technical field of medicine synthesis, specifically, is a kind of compound method of antianginal drug Ismo 20.
[background technology]
5-Ismo 20 (Isosorbide 5-mononitrate, CAS number: 16051-77-7) be the nitrate esters antianginal drug of listing in 1981.Iso Sorbide dinitrate and pannonit have the effect of similar vasodilation and unstriated muscle, and effect is more remarkable than pannonit, and duration of efficacy is long, can obviously increase coronary flow, bring high blood pressure down.The 5-Ismo 20 is a kind of interior metabolism product of two Iso Sorbide dinitrates, advantage such as owing to can directly be absorbed by the body after taking, have that curative effect is fast, longer duration, spinoff are little, and medicinal effect is better than disubstituted nitric ether.
The synthetic common method of 5-Ismo 20 is to use sorbyl alcohol to be raw material; Make the key intermediate Isosorbide through dehydration reaction; After adopting the high vacuum pyrogenic distillation or using methods such as stripping under the high vacuum, hot elevated pressure nitrogen air-flow blow out to obtain highly purified Isosorbide, nitrated again synthesis route.Nitrated direct nitric acid esterification process and the indirect nitric acid esterification process of being divided into.Directly the nitric acid esterification process is to be substrate with highly purified Isosorbide, 2-, and two nitrated backs, 5-position use selective reduction agent reductase 12-position nitro to be hydroxyl.The nitric acid esterification process is the most commonly used with the ethanoyl protection method indirectly, and earlier with highly purified Isosorbide acetylize, nitric acid esterification posthydrolysis 2-position ethanoyl obtains title product again.
Sorbyl alcohol prepares the purification operations of Isosorbide, generally is adopting the high vacuum pyrogenic distillation after the dehydration reaction or using methods of purification such as stripping under the high vacuum, hot elevated pressure nitrogen air-flow blow out.These methods of purification all belong to the unit operation of high energy consumption, and are harsh to working condition and maintenance requirement, certainly will bring the expensive of the finished product, and this also is that domestic manufacturer rarely has the major reason of producing this antianginal drug of 5-Ismo 20.
[summary of the invention]
The objective of the invention is to overcome the deficiency of prior art, a kind of compound method of antianginal drug Ismo 20 is provided.
The objective of the invention is to realize through following technical scheme:
A kind of compound method of antianginal drug Ismo 20, the employing sorbyl alcohol is a raw material, after dehydration reaction, purifies the dehydration reaction mixture with the method for activated carbon filtration; The Isosorbide that obtains carries out direct nitration reaction or indirect nitration reaction, obtains the antianginal drug Ismo 20;
Described direct nitric acid esterification process is to be substrate with highly purified Isosorbide, 2, and two nitrated backs, 5-position use selective reduction agent reductase 12-position nitro to be hydroxyl;
Described indirect nitric acid esterification process is the most commonly used with the ethanoyl protection method, and earlier with highly purified Isosorbide acetylize, after the nitric acid esterification, hydrolysis 2-position ethanoyl obtains title product again.
Compared with prior art, positively effect of the present invention is:
Synthesis technique of the present invention has been avoided highly energy-consuming runnings such as use high vacuum, hot conditions; Simplified synthetic technological condition greatly; Make equipment operation convenient and safe; Production cost also obviously reduces, and is fit to suitability for industrialized production, also is expected to realize the energy-saving and emission-reduction transformation of 5-Ismo 20 existing equipment.
[embodiment]
The embodiment of the compound method of a kind of antianginal drug Ismo 20 of the present invention below is provided.
Embodiment 1
I, get sorbyl alcohol (3.0g) and be dissolved in the 15ml deionized water, place round-bottomed flask, and stir and add the 0.03g tosic acid.Underpressure distillation dehydration reaction 3.5h under 125 ℃/0.1MPa.The cold slightly adding of reaction solution 20ml ETHYLE ACETATE and 10ml methyl alcohol, and regulate the pH value to 6.5-7.0 with 30% sodium hydroxide solution, add anhydrous magnesium sulfate drying then, filter.Make solid phase carrier dress post with the silicagel-active carbon mixture,, and use rinsed reaction solution pressure filtration.With obtaining the liquid Isosorbide of colourless heavy-gravity behind the filtrate steaming removal solvent of collecting.
Isosorbide is joined toluene, and acetate in the mixing solutions of diacetyl oxide, keeps 55 ℃ of temperature.Be cooled to 35 ℃ then, stir and slowly drip the 0.6ml nitrosonitric acid down.Behind reaction 3h under 30 ℃, pour reaction solution in the frozen water into, regulate pH value to 7.0 with the 30%NaOH aqueous solution, separating funnel separates, the organic phase washing.Merge water, with the 2-butanone extraction, organic phase obtains oily matter after steaming and desolventizing.Be dissolved in oily matter in the 50ml deionized water,, leave standstill filtration, obtain white solid 5-Ismo 20 sodium-salt hydrate at 0-5 ℃ of 30%NaOH aqueous solution afterreaction 2h that drips 100ml down.Be dissolved in salt hydrate in the 15ml water, regulate pH value to 6.0, extract with 2-butanone then with Hydrogen chloride.After steaming and desolventize, organic phase obtains the white, needle-shaped crystals 5-Ismo 20 of 0.55g, productive rate 18.3% (in sorbyl alcohol), purity 94.5% (HPLC).
II, get sorbyl alcohol (3.0g) and be dissolved in the toluene, place round-bottomed flask to carry out dehydration reaction.Regulate the pH value to 6.5-7.0 with 30% sodium hydroxide solution, add anhydrous magnesium sulfate drying then, filter.Make solid phase carrier dress post with the silicagel-active carbon mixture,, and use rinsed reaction solution pressure filtration.With obtaining the colourless viscous liquid Isosorbide behind the filtrate steaming removal solvent of collecting.
Isosorbide is joined toluene, and acetate in the mixing solutions of diacetyl oxide, keeps 55 ℃ of temperature.Be cooled to 35 ℃ then, stir and slowly drip the 0.6ml nitrosonitric acid down.Behind reaction 3h under 30 ℃, pour reaction solution in the 50ml frozen water into, regulate pH value to 7.0 with the 30%NaOH aqueous solution, separating funnel separates, the organic phase washing.Merge water, with the 2-butanone extraction, organic phase obtains oily matter after steaming and desolventizing.Be dissolved in oily matter in the 50ml deionized water, at 0-5.Drip the 30%NaOH aqueous solution afterreaction 2h of 100ml under ℃, leave standstill filtration, obtain white solid 5-Ismo 20 sodium-salt hydrate.Be dissolved in salt hydrate in the 15ml water, regulate pH value to 6.0 with Hydrogen chloride, the 2-butanone that adds 60ml then extracts.After steaming and desolventize, organic phase obtains the white, needle-shaped crystals 5-Ismo 20 of 0.48g, productive rate 16% (in sorbyl alcohol).
III, get sorbyl alcohol (3.0g) and be dissolved in the deionized water, place round-bottomed flask, and stir and add the 0.03g tosic acid.Underpressure distillation dehydration reaction 3.5h under 125 ℃/0.1MPa.The cold slightly adding of reaction solution 20ml ETHYLE ACETATE and 10ml methyl alcohol, and regulate the pH value to 6.5-7.0 with 30% sodium hydroxide solution, add anhydrous magnesium sulfate drying then, filter.Make solid phase carrier dress post with the silicagel-active carbon mixture,, and use rinsed reaction solution pressure filtration.With obtaining the colourless viscous liquid Isosorbide behind the filtrate steaming removal solvent of collecting.Isosorbide is joined acetate, in the mixing solutions of diacetyl oxide, carry out acetylization reaction.Be cooled to 35 ℃ then, drip the 0.6ml nitrosonitric acid and carry out nitration reaction.In the KOH aqueous solution, react a night, reaction solution extracts with 2-butanone again.After steaming and desolventize, organic phase obtains the white, needle-shaped crystals 5-Ismo 20 of 0.66g, productive rate 22% (in sorbyl alcohol).
The present invention is that a kind of employing sorbyl alcohol is a raw material, produces the low-carbon (LC) of antianginal drug 5-Ismo 20, the synthesis technique of energy-saving and environmental protection.After the sorbyl alcohol dehydration reaction generates the key intermediate Isosorbide, purify the dehydration reaction mixture with the method for activated carbon filtration, can directly carry out next step nitration reaction behind the filtrate steaming removal solvent.Therefore synthesis technique has been avoided highly energy-consuming runnings such as use high vacuum, hot conditions, has simplified synthetic technological condition greatly, makes equipment operation convenient and safe, and production cost also obviously reduces, and is fit to suitability for industrialized production.
The finished product of the present invention are 5-Ismo 20s, are a kind of antianginal drug.Can directly be absorbed by the body after the 5-Ismo 20 is taken, advantage such as have that curative effect is fast, medicine longer duration, negative interaction are little has more significant medicinal effect than medicines such as disubstituted nitric ether, pannonits.In China and global heart trouble epoch occurred frequently, adopt more environmental protection, low-carbon (LC), energy-conservation green synthesis process to produce this antianginal drug of 5-Ismo 20, have the very society and the economic benefit of reality.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the present invention's design; Can also make some improvement and retouching, these improvement and retouching also should be regarded as in protection scope of the present invention.
Claims (2)
1. the compound method of an antianginal drug Ismo 20 is characterized in that, concrete steps are that the employing sorbyl alcohol is a raw material, after dehydration reaction, purifies the dehydration reaction mixture with the method for activated carbon filtration; The Isosorbide that obtains carries out direct nitration reaction or indirect nitration reaction, obtains the antianginal drug Ismo 20.
2. the method for purification of an Isosorbide is characterized in that, concrete steps do, Isosorbide is purified with the method for activated carbon filtration, obtains Isosorbide.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146527A (en) * | 2015-04-24 | 2016-11-23 | 中国科学院大连化学物理研究所 | A kind of preparation method of dicarboxylic acids isosorbide ester plasticiser |
| CN106632371A (en) * | 2016-08-26 | 2017-05-10 | 山东绿健生物技术有限公司 | Method using dehydrated sorbitol liquid to produce high-purity isosorbide solution |
| CN107011354A (en) * | 2017-04-14 | 2017-08-04 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5 Isosorbide Mononitrate |
| CN110407846A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5- Isosorbide Mononitrate |
| CN112174975A (en) * | 2020-11-09 | 2021-01-05 | 鲁南贝特制药有限公司 | Green refining method of isosorbide mononitrate |
| CN113105470A (en) * | 2021-03-15 | 2021-07-13 | 海南通用康力制药有限公司 | Synthetic method and application of isosorbide mononitrate |
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- 2011-01-24 CN CN2011100258838A patent/CN102603760A/en active Pending
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146527A (en) * | 2015-04-24 | 2016-11-23 | 中国科学院大连化学物理研究所 | A kind of preparation method of dicarboxylic acids isosorbide ester plasticiser |
| CN106632371A (en) * | 2016-08-26 | 2017-05-10 | 山东绿健生物技术有限公司 | Method using dehydrated sorbitol liquid to produce high-purity isosorbide solution |
| CN107011354A (en) * | 2017-04-14 | 2017-08-04 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5 Isosorbide Mononitrate |
| CN107011354B (en) * | 2017-04-14 | 2021-05-11 | 张家港市中医医院 | Preparation method of 5-isosorbide mononitrate |
| CN110407846A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5- Isosorbide Mononitrate |
| CN112174975A (en) * | 2020-11-09 | 2021-01-05 | 鲁南贝特制药有限公司 | Green refining method of isosorbide mononitrate |
| CN113105470A (en) * | 2021-03-15 | 2021-07-13 | 海南通用康力制药有限公司 | Synthetic method and application of isosorbide mononitrate |
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Application publication date: 20120725 |