CN110407846A - A kind of preparation method of 5- Isosorbide Mononitrate - Google Patents
A kind of preparation method of 5- Isosorbide Mononitrate Download PDFInfo
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Abstract
The present invention provides a kind of synthetic methods of 5- Isosorbide Mononitrate.The method includes the steps: using isobide as raw material, TMSCl and nitrate make nitrating agent under the action of alchlor to 5- hydroxyls of anhydro sorbitol selective nitration, and end of reaction pours into reaction solution in ice water, pH value is adjusted to neutrality, precipitating, split-phase are filtered out, water phase organic solvent extracts liquid separation, it is organic to be added to desiccant dryness, active carbon decoloring is concentrated to dryness to get the 5- Isosorbide Mononitrate of high-purity is arrived.The present invention program reaction condition is mild, nitrifies selectivity height, and post-processing is simple, product yield and purity is high, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of 5- Isosorbide Mononitrate.
Background technique
5- Isosorbide Mononitrate (isosorbide 5-mononitrate, 5-ISMN), is 1981 by Germany
The nitrate esters antianginal drug of Bochringer Cnbh company exploitation listing.5-ISMN is Isosorbide Nitrate
The interior metabolism product of (isosorbide dinitrate), without liver first-pass effect after taking, bioavilability is high, has
The advantages that effect is fast, Small side effects, drug effect are high and acting duration is long.5- Isosorbide Mononitrate is adapted to the long-term of coronary heart disease
Continue anginal treatment after treatment, anginal prevention, myocardial infarction, since the eighties listing, has been widely used in facing
Bed, the popular welcome by many patients.The entitled Isosorbide-5-Nitrae of chemistry of 5-ISMN；3,6- bis- dehydrations-D-glucitol -5- list nitro ester,
The entitled Isosorbide-5-Nitrae of English；3,6-Dianllydro-D-Glueitol-5-Mononitrate.Molecular weight is 191, and molecular formula is
C6H9NO6, CAS:16051-77-7.
The synthetic method of 5- Isosorbide Mononitrate has many document reports, and induction and conclusion gets up to be roughly divided into three kinds of sides
Method: direct nitrification process, selective reduction method, and esterification nitrification process.
Wherein direct nitrification process:
5- Isosorbide Mononitrate is synthesized by Hayward L D in nineteen sixty-five earliest, such as 1 institute of chemical equation
Show, in addition wherein patent US3886186, JP5529996, German Pat.No.2221080；I.G.Czizmadia,
L.D.Hayward“Photochem.Photobiol.4657(1965)”、L.D.Hayward“Synthesis of
Isosorbide-5-mono nitrate (Can.J.Chem, 1967, (45): 2191), Lucchi O.De.
“Chemoselective reduction of isosorbide-2,5-dinitrate(GazzettaChimica
Italiana, 1897, (17): the such method of document report earlier such as 173) ".The route is used using isobide as raw material
Fuming nitric aicd directly nitrifies.Isobide is directly nitrified using nitric acid, there is 2- Isosorbide Mononitrate, nitric acid in the substance of generation
Soquad, 5- Isosorbide Mononitrate and unreacted isobide.Reaction mixture is separated by the method that column chromatographs
To pure 5- Isosorbide Mononitrate.But it is very low with the 5- Isosorbide Mononitrate yield that the method generates, and by-product 2,
Isosorbide Mononitrate has the danger of explosion under the process conditions for heating or pressurizeing, and institute is in this way in industrial production
Not applicable.
1. the synthetic route of 5- Isosorbide Mononitrate
([J] " contemporary Chinese is answered in " process modification of Ismo 20 synthesis " by US45843922 and condition generation force etc.
With pharmaceutical journal ", 1998, volume 15, the 5th phase, page 30) text in the factors such as solvent are improved, disclose benzene, second
Acid, the temperature that fuming nitric aicd control nitration reaction is added dropwise under acetic anhydride mixed solvent obtain isosorbidi dinitras sodium-salt hydrate
Yield is respectively 35.8%, 38%, then adjusts pH value to 7 with acid, and obtaining Ismo 20 yield is respectively 73.5%,
83%.
Xing Huihai etc. " synthesis of 5-ISMN " ([J] " Chinese Journal of Pharmaceuticals " 2011,42 (7):
It 489-490) is purified after sorb dehydration of alcohols without high temperature high vacuum distillation in a text, but passes through silicagel-active carbon and filter, filtrate
After solvent is evaporated off, directly nitrified using toluene-acetic acid-acetic anhydride mixed liquor as solvent with fuming nitric aicd, through sodium hydroxide solution
Processing, hydrochloric acid tune pH value 6.0 obtain product, and total recovery is 18.3% (in terms of sorbierite).
It is esterified nitrification process
For document using sorbierite as starting material, sulfuric acid is catalyst, and dimethylbenzene is reaction dissolvent.Author use dimethylbenzene for
Solvent, is primarily due to dimethylbenzene and water may make up binary azeotropic system, can remove the water of production constantly by this characteristic, from
And promote the progress of dehydration.Pure isobide (62%) is obtained by high temperature high vacuum distillation.Later, with methylene chloride
For solvent, pyridine is catalyst, and acetic anhydride is that acylating reagent carries out acylation reaction, is not needed to be separated directly to obtained reaction substrate
Carry out nitration reaction.Author is nitrification solvent with fuming nitric aicd/acetic acid/acetic anhydride.Last potassium hydroxide/ethanol hydrolysis obtains 5-
Isosorbide Mononitrate.Reaction equation is as indicated with 2:
2. the synthetic route of 5-ISMN
In conclusion being had using nitrification process in the prior art largely has 2- Isosorbide Mononitrate, Isosorbide
Ester is mixed in product, brings difficulty to purifying, while also bringing no small pressure to environmental protection, although selective reduction method
There are also the techniques such as esterification nitrification process to be improved, but still suffers from above-mentioned problem, and technique is tediously long, and yield is low, purity
The problems such as poor.Directly nitrification route is short, but nitrating agent selective nitration is difficult, therefore there is an urgent need to develop a kind of high selections
Property nitration method solves problems.
Summary of the invention
It is an object of the invention to be directed to the drawbacks described above of prior art technology, provide a kind of in nitrification isobide process
In, method that selective nitration obtains high-purity 5- Isosorbide Mononitrate.
Inventor makees nitrating agent in alchlor using TMSCl and nitrate by in-depth study and exploration, discovery
When nitrifying under effect to isobide, selective nitration effect is poor.Inventor further study show that by isobide with
The hybrid reaction of TMSCl and appropriate bases after a certain period of time, adds nitrate and alchlor is nitrified.It is nitrified by control
The 5- Isosorbide Mononitrate of high-purity can be obtained in the factors such as temperature, the ratio of TMSCl and nitrate and dosage.Post-processing letter
It is single, after fully reacting, water quenching is added to go out, adjusting pH value is neutrality, is filtered, filtrate liquid separation, and the extraction of water phase organic solvent is organic relevant
It is dry, it is concentrated to dryness to obtain product, the purity of product greatly improves, and has reached the purpose of the present invention, and inventor is also to reaction reagent, anti-
The condition for answering the influences such as temperature to react has made further research and verifying.
Specifically, the present invention is achieved through the following technical solutions:
Isobide, TMSCl and appropriate organic base low-temperature mixed are stirred to react for a period of time, under temperature control, add three
Aluminium chloride and nitrate keep low temperature to end of reaction, reaction solution are poured into ice to 5- hydroxyls of isobide selective nitration
In water, adjusting pH value is neutrality, filters out precipitating, split-phase, and water phase organic solvent extracts liquid separation, and organic desiccant that is added to is done
Dry, active carbon decoloring is concentrated to dryness to get the 5- Isosorbide Mononitrate of high-purity is arrived；
Reaction equation is as follows:
The quality of the isobide and the mass ratio of TMSCl are as follows: 1:0.5~1.5；It is preferred that are as follows: 1:1.12.
The alkali is one of triethylamine, pyridine, diethylamine, propylamine, isopropylamine, di-iso-butylmanice or several；It is excellent
Select triethylamine.
Described is stirred to react a period of time are as follows: 0.2h~2h；Preferred reaction time is 0.5h.
The mass ratio of the material of the isobide and organic base are as follows: 1:1.0~1.1；It is preferred that are as follows: 1:1.0.
The nitrate is one of sodium nitrate, potassium nitrate or combination.
The mass ratio of the material of the isobide and nitrate are as follows: 1:1.0~1.5；It is preferred that are as follows: 1:1.1.
The quality of the isobide and the mass ratio of alchlor are 1:0.1~0.5；It is preferred that are as follows: 1:0.18.
The organic solvent is that the one or more of ethyl acetate, methyl acetate, methylene chloride, chloroform etc. are molten
Agent.
The quality of the active carbon and the volume ratio of organic solvent are as follows: 1:20~100, g/ml；It is preferred that are as follows: 1:50, g/
ml。
The reaction temperature are as follows: -20 DEG C~10 DEG C；It is preferred that are as follows: -10 DEG C~5 DEG C.
The present invention achieves following technical effect compared with prior art:
(1) use nitrate and TMSCl (trim,ethylchlorosilane) system as nitrating agent, reaction condition is mild, generation
5- Isosorbide Mononitrate purity is higher, and selectivity is higher, and generation silicon ether can be recycled by liquid separation, easy to operate, right
Environmental pollution is smaller.
(2) after the reaction was completed, purified water is added in reaction solution, and post-processing will not generate more " three wastes ".
(3) product yield is up to 90% or more；And product does not have to be purified by column chromatography, at modes such as salt.
(4) products obtained therefrom does not need to refine；After organic extractant phase is dry, active carbon decoloring, being directly thickened to do can be obtained
To qualified finished product, multiple fine manufacture is avoided to lose at product.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, these embodiments are only used for the mesh of illustration
, it should not be construed as limiting the invention, the obvious improvement and modification that those skilled in the art are the present invention
Also within that scope of the present invention.
Embodiment 1:
46g isobide, 32g triethylamine, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, drop
Temperature is stirred to react 0.5h to -5 DEG C or so, and 8.3g alchlor is added, then 26.78g sodium nitrate solid is added portionwise, adds
It keeps temperature not higher than 0 DEG C during entering, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, reaction
Completely, reaction solution is poured into 400ml ice water, potassium hydroxide solution adjust pH value be neutrality, filter, filtrate liquid separation, water phase according to
The secondary ethyl acetate with 200mL, 100ml, 100mL extracts, and merges organic phase, and the dry 4h of 20g anhydrous magnesium sulfate is added, filters,
8.0g active carbon heating decoloration 30min is added in filtrate, filters out active carbon, solution is concentrated to dryness, and obtains solid 57.6g, HPLC
Detecting purity is 99.84%, yield 96.0%.
Embodiment 2:
46g isobide, 32g triethylamine, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, drop
Temperature is stirred to react 0.5h to -5 DEG C or so, and 8.3g alchlor is added, then 31.82g potassium nitrate solid is added portionwise, adds
It keeps temperature not higher than 0 DEG C during entering, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, reaction
Completely, reaction solution is poured into 400ml ice water, potassium hydroxide solution adjust pH value be neutrality, filter, filtrate liquid separation, water phase according to
The secondary ethyl acetate with 200mL, 100ml, 100mL extracts, and merges organic phase, and the dry 4h of 20g anhydrous magnesium sulfate is added, filters,
4.0g active carbon heating decoloration 30min is added in filtrate, filters out active carbon, and solution is concentrated to dryness, and obtains solid 57g, HPLC inspection
Surveying purity is 99.74%, yield 95.0%.
Embodiment 3:
46g isobide, 23g diethylamine, 69g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, cooling
To -5 DEG C or so, it is stirred to react 0.2h, 8.3g alchlor is added, then 40.17g sodium nitrate solid is added portionwise, is added
It keeps temperature to be not higher than 0 DEG C in the process, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, has reacted
Entirely, reaction solution is poured into 400ml ice water, it is neutrality that potassium hydroxide solution, which adjusts pH value, is filtered, filtrate liquid separation, water phase is successively
It is extracted with the ethyl acetate of 200mL, 100ml, 100mL, merges organic phase, the dry 4h of 20g anhydrous magnesium sulfate is added, filters, filter
8.0g active carbon heating decoloration 30min is added in liquid, filters out active carbon, and solution is concentrated to dryness, and obtains solid 54.2g, HPLC inspection
Surveying purity is 99.70%, yield 90.3%.
Embodiment 4:
46g isobide, 32g triethylamine, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, drop
Temperature is stirred to react 2h to 10 DEG C or so, and 23g alchlor is added, then 31.82g potassium nitrate solid is added portionwise, was added
It keeps temperature to be not higher than 10 DEG C in journey, continues to stir, addition finishes, and keeps the temperature 10 DEG C or so reaction 2h, HPLC detections, has reacted
Entirely, reaction solution is poured into 400ml ice water, it is neutrality that potassium hydroxide solution, which adjusts pH value, is filtered, filtrate liquid separation, water phase is successively
It is extracted with the ethyl acetate of 200mL, 100ml, 100mL, merges organic phase, the dry 4h of 20g anhydrous magnesium sulfate is added, filters, filter
17.6g active carbon heating decoloration 30min is added in liquid, filters out active carbon, and solution is concentrated to dryness, and obtains solid 57g, HPLC detection
Purity is 99.74%, yield 95.0%.
Embodiment 5:
46g isobide, 35.2g triethylamine, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension,
- 20 DEG C or so are cooled to, 0.5h is stirred to react, 8.3g alchlor is added, then 26.78g sodium nitrate solid is added portionwise,
It keeps temperature to be not higher than 0 DEG C in adition process, continues to stir, addition finishes, and keeps the temperature -20 DEG C or so reaction 2h, HPLC detections, instead
Reaction solution should be poured into 400ml ice water completely, it is neutrality that potassium hydroxide solution, which adjusts pH value, is filtered, filtrate liquid separation, water phase
It is successively extracted with the methylene chloride of 200mL, 100ml, 100mL, merges organic phase, the dry 4h of 20g anhydrous magnesium sulfate is added, takes out
Filter, filtrate are added 17.6g active carbon heating decoloration 30min, filter out active carbon, and solution is concentrated to dryness, and obtain solid 56.1g,
It is 99.72% that HPLC, which detects purity, yield 93.5%.
Embodiment 6:
46g isobide, 35.2g triethylamine, 23.0g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension,
- 5 DEG C or so are cooled to, 0.5h is stirred to react, 8.3g alchlor is added, then 31.82g potassium nitrate solid is added portionwise,
It keeps temperature to be not higher than 0 DEG C in adition process, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, instead
Reaction solution should be poured into 400ml ice water completely, it is neutrality that potassium hydroxide solution, which adjusts pH value, is filtered, filtrate liquid separation, water phase
The chloroform extraction for successively using 200mL, 100ml, 100mL, merges organic phase, and the dry 4h of 20g anhydrous magnesium sulfate is added, takes out
Filter, filtrate are added 8.0g active carbon heating decoloration 30min, filter out active carbon, and solution is concentrated to dryness, and obtain solid 54.8g,
It is 99.78% that HPLC, which detects purity, yield 91.3%.
Embodiment 7:
46g isobide, 24.9g pyridine, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, drop
Temperature is stirred to react 0.5h to -5 DEG C or so, and 8.3g alchlor is added, then 47.7g potassium nitrate solid is added portionwise, and is added
It keeps temperature to be not higher than 0 DEG C in the process, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, has reacted
Entirely, reaction solution is poured into 400ml ice water, it is neutrality that potassium hydroxide solution, which adjusts pH value, is filtered, filtrate liquid separation, water phase is successively
It is extracted with the methyl acetate of 200mL, 100ml, 100mL, merges organic phase, the dry 4h of 20g anhydrous magnesium sulfate is added, filters, filter
8.0g active carbon heating decoloration 30min is added in liquid, filters out active carbon, and solution is concentrated to dryness, and obtains solid 55.2g, HPLC inspection
Surveying purity is 99.71%, yield 92.0%.
Embodiment 8:(comparative example)
46g isobide, 51.5g trim,ethylchlorosilane are added in there-necked flask, stirring is in suspension, is cooled to -5 DEG C of left sides
The right side is stirred to react 0.5h, and 8.3g alchlor is added, then 26.78g sodium nitrate solid is added portionwise, protects in adition process
Temperature is held not higher than 0 DEG C, continues to stir, addition finishes, and keeps the temperature -5 DEG C or so reaction 2h, HPLC detections, and fully reacting will react
Liquid pours into 400ml ice water, potassium hydroxide solution adjust pH value be neutrality, filter, filtrate liquid separation, water phase successively use 200mL,
The ethyl acetate of 100ml, 100mL extract, and merge organic phase, and the dry 4h of 20g anhydrous magnesium sulfate is added, filters, filtrate is added
8.0g active carbon heating decoloration 30min, filters out active carbon, and solution is concentrated to dryness, and obtains solid 32.4g, and HPLC detects purity
It is 99.50%, yield 54.0%.
Claims (10)
1. a kind of preparation method of 5- Isosorbide Mononitrate, which is characterized in that this method comprises the following steps:
Isobide, TMSCl and appropriate organic base low-temperature mixed are stirred to react for a period of time, under temperature control, add tri-chlorination
Aluminium and nitrate keep low temperature to after completion of the reaction, reaction solution are poured into ice water to 5- hydroxyls of isobide selective nitration
In, adjusting pH value to neutrality filters out precipitating, and split-phase, water phase organic solvent extracts liquid separation, and it is organic to be added to desiccant dryness,
Active carbon decoloring is concentrated to dryness to get the 5- Isosorbide Mononitrate of high-purity is arrived；
Reaction equation is as follows:
2. preparation method according to claim 1, which is characterized in that the quality of the isobide and the matter of TMSCl
Measure ratio are as follows: 1:0.5~1.5.
3. preparation method according to claim 1, which is characterized in that the alkali is triethylamine, pyridine, diethylamine, third
One of amine, isopropylamine, di-iso-butylmanice are several.
4. preparation method according to claim 1, which is characterized in that the amount of the substance of the isobide and organic base
Than are as follows: 1:1.0~1.1.
5. preparation method according to claim 1, which is characterized in that the nitrate is sodium nitrate, in potassium nitrate
A kind of or combination.
6. preparation method according to claim 1, which is characterized in that the amount of the substance of the isobide and nitrate
Than are as follows: 1:1.0~1.5.
7. preparation method according to claim 1, which is characterized in that the quality of the isobide and alchlor
Mass ratio is 1:0.1~0.5.
8. preparation method according to claim 1, which is characterized in that the organic solvent is ethyl acetate, acetic acid first
One or more kinds of solvents of ester, methylene chloride, chloroform etc..
9. preparation method according to claim 1, which is characterized in that the quality of the active carbon and the body of organic solvent
Product ratio are as follows: 1:20~100, g/ml.
10. preparation method according to claim 1, which is characterized in that the reaction temperature are as follows: -20 DEG C~10 DEG C；It is described
Be stirred to react a period of time are as follows: 0.2h~2h.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111007181A (en) * | 2019-12-30 | 2020-04-14 | 鲁南制药集团股份有限公司 | Method for detecting isosorbide mononitrate |
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| CN111007181A (en) * | 2019-12-30 | 2020-04-14 | 鲁南制药集团股份有限公司 | Method for detecting isosorbide mononitrate |
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