CN102285987A - Novel preparation process of oxymatrine - Google Patents
Novel preparation process of oxymatrine Download PDFInfo
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- CN102285987A CN102285987A CN 201110232387 CN201110232387A CN102285987A CN 102285987 A CN102285987 A CN 102285987A CN 201110232387 CN201110232387 CN 201110232387 CN 201110232387 A CN201110232387 A CN 201110232387A CN 102285987 A CN102285987 A CN 102285987A
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Abstract
The invention provides a preparation method of oxymatrine. The preparation method comprises a series of steps such as dissolution, oxidation reaction, crystallization, filtration, drying and the like by taking matrine as a raw material. The obtained oxymatrine is high in content, low in cost and high in yield. The preparation method of the oxymatrine is novel in process and good in stability, is suitable for industrial production and has a strong practicability.
Description
Technical field
The present invention relates to a kind of Oxymatyine preparation method, belong to the biomedicine field category with antivirus action.
Background technology
Hepatitis B is modal in the world transmissible disease, is a kind of disease that is caused by hepatitis B virus (HBV).The whole world has 3.5～400,000,000 people's hepatitis b virus infections approximately, more than the octuple of number up to the HIV-positive.Hepatitis b virus infected liver cirrhosis and the hepatocellular carcinoma (HCC) of bringing out has 1,000,000 people to die from hepatitis B dependency hepatic diseases every year.
Oxymatyine, have another name called kurarinone, it is a kind of alkaloid compound that extraction separation obtains from sophora alapecuroides with very strong hepatitis virus resisting activity, can reduce the content of interior HBsAg of hepatitis B virus transgenic mice liver and HBcAg, the clinical treatment that is mainly used in chronic hepatitis B, have better curative effect and security, obtained using very widely.
The method for preparing at present Oxymatyine mostly is to be raw material with the matrine, by hydrogen peroxide oxidation, remove steps such as excessive hydrogen peroxide, crystallization, recrystallization and carry out, though can prepare Oxymatyine, have that long reaction time, conversion rate of products are low, hydrogen peroxide residue is difficult to deficiencies such as removal.
At application number is in the patent of invention of 200510113090.6 " clean kurarinol producing process " by name, disclosing a kind of is raw material with the matrine, technological process by oxidation, cancellation, extraction reclaim matrine, concentrate, steps such as heavy molten, the filtration of polar solvent, condensing crystal, separation oven dry, crude product refining form, select to add the cancellation catalyzer in this patent of invention, its essence adds the reductibility compound exactly, for the decomposition of excessive hydrogen peroxide in the promote the oxidation reaction process.Though this method can shorten the time of decomposing hydrogen dioxide solution, owing to also added other chemical ingredientss simultaneously, need separate removal, so subsequent disposal is comparatively complicated, has also increased production cost.
At application number is in the patent of invention of 00109240.5 " a kind of kurarinone and preparation technology thereof " by name, a kind of preparation technology of kurarinone is provided, this technology with matrine through oxidation, extraction, concentrate, processing steps such as backflow, suction filtration, finally make the kurarinone crystallization.This technology is to adopt the method for hydrogen peroxide oxidation reaction to prepare kurarinone equally, and is just slightly different on the method for handling hydrogen peroxide.
At application number is in the patent of 200510048243.3 " being produced the method for high purity matrine oxide by kuh-seng " by name, adopted that oxidation prepares Oxymatyine in 5～30% aqueous hydrogen peroxide solution, reaction is finished and is added the excessive hydrogen peroxide of reductive agent reduction again, obtains Oxymatyine at last.This method remains the method that adopts hydrogen peroxide oxidation, removes hydrogen peroxide again and prepares Oxymatyine.
At application number is in the patent of 03137048.9 " preparation method of Oxymatyine " by name, is that employing is water-soluble with matrine equally, adds 30% hydrogen peroxide, and the method for repeated hydrogenation sodium oxide thermal degradation hydrogen peroxide prepares the Oxymatyine product.
More than various preparation methods' common ground all be in matrine, to add hydrogen peroxide to carry out oxidation, adopt different technique means to decompose again to remove hydrogen peroxide, though in the control of reaction parameter, remove some difference on the method for hydrogen peroxide, its essence all round hydrogen peroxide oxidation, decompose these two steps of hydrogen peroxide and carry out.Because hydrogen peroxide can not be residual in the Oxymatyine product, therefore the removal of hydrogen peroxide requires very thorough, in above-mentioned disclosed method, adopt methods such as adding reductive agent, extraction, adding sodium hydroxide to remove hydrogen peroxide in the reaction solution respectively, caused shortcomings such as complex process, the production cycle is long, product yield is low.
Ozone is universally acknowledged broad-spectrum high efficacy disinfection sanitizer, Duoed a Sauerstoffatom than oxygen molecule in its molecule, chemical property is active especially, it is a kind of strong oxidizer, has good oxidisability at finite concentration, and use the back without any poisonous residual, and can not form secondary pollution, be described as " oxygenant and the sterilizing agent that clean most ".Ozonizer is that a kind of high-tension current of certain frequency that uses is made the high-voltage corona electric field, makes in the electric field or the oxygen molecule generation electrochemical reaction around the electric field, thereby makes the equipment of ozone.Along with the raising of ozonizer production technology level, it has obtained application more and more widely in fields such as industrial building-up reactions, sterilization, environmental protection treatment.
The present invention is on the basis of big quantity research, uses still not a kind of oxygenant of ozone, and self is easy to resolve into the principle of oxygen, and a kind of novel method that adopts ozone oxidation to prepare Oxymatyine is provided.Because excessive ozone at room temperature can be decomposed into oxygen, therefore adopt present method to prepare Oxymatyine, not only efficiently solve the problem that hydrogen peroxide residue is difficult to decompose in original method, and technique process is simplified greatly, the production cycle shortens greatly, production process is simplified simultaneously, product loss is little, the yield height.
The object of the invention is to select new oxygenant for use, is raw material with the matrine, produces content height, Oxymatyine that impurity is few.Present method is to the breakthrough of a matter of technology in the past, and process cycle is short, and low, the low-carbon environment-friendly of cost has good application prospects, has very strong practicality.
In disclosed document and patent, also there is not related to the present invention or similar report.
Summary of the invention
Ozone of the present invention is oxygenant, is raw material with the matrine, produces content height, Oxymatyine that impurity is few.Solved long, the residual shortcoming that is difficult to remove of oxygenant of explained hereafter cycle in the past.
According to the embodiment of comparative optimization of the present invention, produce the method for Oxymatyine and form by following steps:
(1) gets matrine, add the appropriate amount of organic dissolving, be heated to certain temperature.
(2) feed certain density ozone gas in matrine solution and carry out oxidizing reaction, control flow velocity and temperature of reaction behind the reaction certain hour, stop ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization for some time at a certain temperature.
(4) filter, get crystallization, drying promptly gets Oxymatyine.
" organic solvent " described in the above-mentioned steps (1) is meant organic solvents such as ethanol, methyl alcohol, acetone, ethyl acetate, Virahol.Because matrine is little polar component, is soluble in organic solvent, is insoluble in water, and Oxymatyine is the high polarity material, be insoluble in organic solvent, therefore select suitable organic solvent not only can dissolve matrine, and be to get ready for the direct crystallization of reacted Oxymatyine; The consumption of organic solvent is 2～10 times of amounts of matrine weight, is preferably 4 times of amounts; The temperature of solution is 30～60 ℃, is preferably 40 ℃.
The concentration that feeds ozone in the step (2) is 0.1～100g/L, is preferably 5g/L, and ozone concn is too big, and oxidizing reaction will be too violent, produces minor by-products impurity simultaneously, and ozone concn crosses that low then speed of response is slow, and efficient is low.By repeatedly testing relatively, preferred 5g/L is the reaction optimum concn; Feeding ozone gas speed is 0.1～10m
3/ h is preferably 2m
3/ h, it is insufficient that ventilation speed is then reacted too soon, causes the ozone loss, and ventilation speed is crossed and is then reduced production efficiency slowly, through test of many times, preferred 2m
3/ h is an optimum response speed, and this moment, reacting balance carried out, and is most effective; The temperature of control reaction solution is 30～60 ℃, is preferably 40 ℃; Temperature is too high, and the decomposition of ozone is quickened, and causes damage, and temperature crosses that low then reaction process is slower, influences efficient.Through test of many times, preferred 40 ℃ is optimal reaction temperature, and this moment, the utilization ratio of ozone was higher, and the reaction times is short; Reaction times is 0.5～5 hour, is preferably 1 hour.
The crystalline temperature is-10～30 ℃ in the step (3), is preferably 10 ℃.The too high then crystallization of temperature is insufficient, influences the product yield, and temperature crosses that low then impurity-eliminating effect is poor slightly, influence quality product, and by verification experimental verification, preferred 10 ℃ is the Tc of the best; Crystallization time is 2～24 hours, preferred 12 hours.The too short then crystallization of crystallization time is insufficient, influences the product yield, and the long impurity of then separating out of crystallization time is on the high side, influences quality product, investigates by test, and preferred 12 hours is best crystallization time.
In the step (4), the exsiccant mode can be constant pressure and dry and drying under reduced pressure, is preferably drying under reduced pressure.The Oxymatyine fusing point is lower, destroys easily under the hot conditions, therefore selects the drying mode of low-temperature reduced-pressure can guarantee the quality of product.
Ozone in this testing program produces by KCF type ozonizer, and this ozonizer is a kind of ozone generating apparatus of routine, can control the concentration and the flow of ozone generation by regulating frequency and control valve.This section illustration purpose is for the generation equipment source of explaining the used ozone of the present invention does not have particular requirement, thereby further specifies practicality of the present invention, should not be construed as the restriction to claim of the present invention.
According to technique scheme, adopt scientific and feasible method with matrine through series of steps such as dissolving, ozone oxidation reaction, crystallization removal of impurities, dryings, made purity height, Oxymatyine that cost is low, content can reach 98%～99.9%.
Technical scheme provided by the invention is verified through many batches of suitability for industrialized production, and technology stability, good reproducibility are quality controllable, have very strong practicality.
Embodiment
Used matrine meets the regulation of State Food and Drug Administration's drug standard in following examples; Used solvent is an analytical pure, and ozonizer is the KCF-Z type.
Embodiment 1
(1) gets matrine 20kg, add ethanolic soln 80kg dissolving, and be heated to 40 ℃.
(2) feeding concentration in matrine solution is that the ozone gas of 5g/L carries out oxidizing reaction, and the control flow velocity is 2m
3/ h and temperature of reaction were reacted after 1.5 hours, stopped ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization 10 hours under 5 ℃.
(4) filter, get crystallization,, promptly get Oxymatyine 19.2kg in 60 ℃ of drying under reduced pressure.After testing, content is 99.2%.
Embodiment 2
(1) gets matrine 25kg, add acetone soln 75kg dissolving, and be heated to 35 ℃.
(2) feeding concentration in matrine solution is that the ozone gas of 2g/L carries out oxidizing reaction, and the control flow velocity is 5m
3/ h and temperature of reaction were reacted after 2.0 hours, stopped ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization 12 hours under 10 ℃.
(4) filter, get crystallization,, promptly get Oxymatyine 23.9kg in 50 ℃ of drying under reduced pressure.After testing, content is 99.5%.
Embodiment 3
(1) gets matrine 20kg, add aqueous isopropanol 75kg dissolving, and be heated to 45 ℃.
(2) feeding concentration in matrine solution is that the ozone gas of 4g/L carries out oxidizing reaction, and the control flow velocity is 5m
3/ h and temperature of reaction were reacted after 0.5 hour, stopped ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization 18 hours under 0 ℃.
(4) filter, get crystallization,, promptly get Oxymatyine 19.4kg in 50 ℃ of drying under reduced pressure.After testing, content is 98.2%.
Embodiment 4
(1) gets matrine 50kg, add ethyl acetate solution 125kg dissolving, and be heated to 40 ℃.
(2) feeding concentration in matrine solution is that the ozone gas of 2g/L carries out oxidizing reaction, and the control flow velocity is 10m
3/ h and temperature of reaction were reacted after 1 hour, stopped ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization 20 hours under-5 ℃.
(4) filter, get crystallization,, promptly get Oxymatyine 46.4kg in 55 ℃ of drying under reduced pressure.After testing, content is 98.2%.
Claims (5)
1. the preparation method of an Oxymatyine, be made up of following several steps:
(1) gets matrine, add the appropriate amount of organic dissolving, be heated to certain temperature.
(2) feed certain density ozone gas in matrine solution and carry out oxidizing reaction, control flow velocity and temperature of reaction behind the reaction certain hour, stop ventilation.
(3) reaction solution is put coldly, leaves standstill crystallization for some time at a certain temperature.
(4) filter, get crystallization, drying promptly gets Oxymatyine.
2. the preparation method of Oxymatyine according to claim 1 is characterized in that " organic solvent " is meant organic solvents such as methyl alcohol, ethanol, acetone, ethyl acetate, Virahol in the step (1); The consumption of organic solvent is 2～10 times of amounts of matrine weight, is preferably 4 times of amounts; The temperature of solution is 30～60 ℃, is preferably 40 ℃.
3. the preparation method of Oxymatyine according to claim 1 is characterized in that the concentration of feeding ozone in the step (2) is 0.1～100g/L, is preferably 5g/L; Feeding ozone gas speed is 0.1～10m
3/ h is preferably 2m
3/ h; The temperature of control reaction solution is 30～60 ℃, is preferably 40 ℃; Reaction times is 0.5～5 hour, is preferably 1 hour.
4. the preparation method of Oxymatyine according to claim 1 is characterized in that the crystalline temperature is-10～30 ℃ in the step (3), is preferably 10 ℃; Crystallization time is 2～24 hours, preferred 12 hours.
5. the preparation method of Oxymatyine according to claim 1 is characterized in that the exsiccant mode can be constant pressure and dry and drying under reduced pressure, is preferably drying under reduced pressure in the step (4).
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| CN 201110232387 CN102285987A (en) | 2011-08-15 | 2011-08-15 | Novel preparation process of oxymatrine |
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| CN 201110232387 CN102285987A (en) | 2011-08-15 | 2011-08-15 | Novel preparation process of oxymatrine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473829A (en) * | 2003-06-02 | 2004-02-11 | 平 刘 | Process for preparing oxymatrine |
| CN1772752A (en) * | 2005-10-13 | 2006-05-17 | 宁夏大学 | Clean kurarinol producing process |
| CN1793142A (en) * | 2005-12-27 | 2006-06-28 | 中国科学院山西煤炭化学研究所 | Process for producing high purity matrine oxide by kuh-seng |
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2011
- 2011-08-15 CN CN 201110232387 patent/CN102285987A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473829A (en) * | 2003-06-02 | 2004-02-11 | 平 刘 | Process for preparing oxymatrine |
| CN1772752A (en) * | 2005-10-13 | 2006-05-17 | 宁夏大学 | Clean kurarinol producing process |
| CN1793142A (en) * | 2005-12-27 | 2006-06-28 | 中国科学院山西煤炭化学研究所 | Process for producing high purity matrine oxide by kuh-seng |
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Application publication date: 20111221 |