CN102924376A - Method for preparing high-purity bulleyaconitine A - Google Patents
Method for preparing high-purity bulleyaconitine A Download PDFInfo
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- CN102924376A CN102924376A CN2012104946780A CN201210494678A CN102924376A CN 102924376 A CN102924376 A CN 102924376A CN 2012104946780 A CN2012104946780 A CN 2012104946780A CN 201210494678 A CN201210494678 A CN 201210494678A CN 102924376 A CN102924376 A CN 102924376A
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Abstract
The invention discloses a method for preparing high-purity bulleyaconitine A. The method comprises the following steps of: soaking a fresh radix aconiti agrestis root in acid aqueous solution, performing homogenate extraction and cavitation mixing solid-liquid extraction, collecting and concentrating the filtrate, and respectively performing gradient elution to obtain a crude bulleyaconitine A product through ion exchange resin column chromatography and macroporous adsorption resin column chromatography; and uniformly mixing crude bulleyaconitine A product and ethanol aqueous solution, dissolving in a water bath, cooling the filtrate to room temperature, standing and crystallizing at the temperature of 4 DEG C, repeatedly washing the crystal by using the ethanol aqueous solution, and obtaining a final product. According to the method, crushing and extracting are finished in one step through a homogenization method, and the method has the advantages of zero dust and simple flow. By adoption of a negative-pressure cavitation extraction technology, the mass transfer rate is improved, heating is not required, and the production period is shortened; and moreover, the reagents used in the whole process are ethanol and water, the organic solvent amount is greatly reduced, the production cost can be reduced, the environmental pollution is reduced, and the method has good application prospect.
Description
Technical field
The invention belongs to plant purification techniques field, be specifically related to a kind of method for preparing high-purity bulleyaconitine A of from fresh radix aconiti agrestis, extracting.
Background technology
Ranunculaceae aconitum plant radix aconiti agrestis and monkshood are the traditional Chinese medicine materials of China, are usually used in treating rheumatism and the acute diseases such as rheumatoid arthritis and sciatica.Its decocting liquid once was used to alleviate the pain of patients with advanced cancer.And one of bulleyaconitine A activeconstituents that to be it main has central analgesia and periphery analgesic double pharmacological action, and analgesia time is long, without addicted characteristics.Its side effect is little, to each vitals without obviously damage, without teratogenesis, the at present clinical treatment that is mainly used in the acute and chronic pain illness such as zoster and cancer of late stage pain, rheumatism and rheumatoid arthritis, scapulohumeral periarthritis, optimum arthrodynia, effect is remarkable.
Bulleyaconitine A molecular formula C
35H
49O
10N, molecular weight 643.77 for colourless rib shape crystal or white powder, is soluble in ether, trichloromethane, the ethanol.Result of study shows its solubleness in water little (166.78 μ g/mL) and unstable, at room temperature easily degrades.And its solubleness and stability increase with the reduction of pH value.
" Chinese material plant medicine " and Luo Shide etc. utilize liquid ammonia alkalinization in " chemical journal ", benzene extraction, and chloroform extraction, alumina column chromatography, the mode of ether-benzene wash-out is separated bulleyaconitine A.Be the extraction solvent because it uses high carcinogens benzene and explosive solvent ether, and production cost is high, safety is difficult to control.Mention among the patent CN101830849B and use alkaline soak that gasoline or sherwood oil refluxing extraction are that eluent carries out column chromatography with gasoline, ethyl acetate, triethylamine mixed solvent again.Other has and mentions among the patent CN101555227B with the sour water equal solvent and extracting, and transfer pH, ethyl acetate or chloroform extraction are that eluent carries out column chromatography with gasoline, sherwood oil, acetone and diethylamine equal solvent again.The consumption of chromatography column packing is large in the bulleyaconitine A preparation process at present, uses in a large number inflammable organic solvent, makes production cost high, and has potential safety hazard, easily causes environmental pollution simultaneously.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide a kind of low consumption environment protection ground to prepare the method for high-purity bulleyaconitine A.By the application of macroporous resin and ion exchange resin, take water and ethanol as eluent, reduce the usage quantity of organic solvent, thereby reduce production costs and environmental contamination reduction.
Purpose of the present invention is achieved through the following technical solutions.
Except as otherwise noted, percentage ratio of the present invention is mass percent.
A kind of preparation method of high-purity bulleyaconitine A may further comprise the steps:
(1) get fresh radix aconiti agrestis piece root, clean with clear water first, press solid-liquid ratio (g/mL) the immersion radix aconiti agrestis 24 hours of 1:2～1:4 with aqueous acid again, described aqueous acid is HCl or the H of concentration 0.1mol/L～0.4mol/L
2SO
4The aqueous solution;
(2) soaked radix aconiti agrestis piece root is put into refiner, add described aqueous acid by the solid-liquid ratio of 1:6～1:10,10～20min is extracted in homogenate, filters afterwards, and collects filtrate;
(3) material after homogenate is extracted is pressed 1:6～1:10 solid-liquid ratio again and is added aqueous acid, and negative pressure cavitation DL liquid-solid extraction 4 times extracts 30～60min at every turn, filters and collect filtrate;
(4) merge twice filtrate, concentrated, behind ion exchange resin column chromatography and macroporous adsorbent resin column chromatography gradient elution, get respectively again the bulleyaconitine A crude product;
(5) solid-liquid ratio by 1:10～1:20 mixes bulleyaconitine A crude product and aqueous ethanolic solution, and the volume fraction 65%～80% of aqueous ethanolic solution is bathed dissolving at 40 ℃～60 ℃ Water Unders; Filter, filtrate is cooled to place under 4 ℃ of conditions after the room temperature again leaves standstill crystallization, and crystal aqueous ethanolic solution repetitive scrubbing gets the finished product.
Wherein, the described negative pressure cavitation DL of step (3) liquid-solid extraction carries out under negative pressure 0.06～0.1MPa suction condition.
Filter cloth is all adopted in filtration described in each step, and throttling component 0.02～10 μ m particle adopts negative pressure 0.06～0.1MPa suction filtration, and rotor stirs with the speed of rotating speed 1800-2400r/min simultaneously, stops up to prevent precipitation.
The employed sorbent material of the described column chromatography of step (4) is Zeo-karb and polystyrene type macroporous adsorbent resin.
The eluent of described Zeo-karb is a kind of of NaCl solution, HCl solution, alkaline ethanol solution or ammonia soln; The eluent of polystyrene type macroporous adsorbent resin is water or aqueous ethanolic solution.
The present invention compared with prior art has following advantage:
1. the present invention has realized pulverizing, has extracted a step and finish with the homogenate method, has replaced the working method of the multi-steps such as traditional material dry ground, heating and refluxing extraction, has without dust, the simple advantage of flow process.
2. the present invention adopts the negative pressure cavitation extractive technique, improves rate of mass transfer, need not heating, shortens the production cycle.
3. the present invention uses macroporous resin and ion exchange resin is the column chromatography filler, can reuse.Simultaneously whole technique agents useful for same is the second alcohol and water, greatly reduces the use of organic solvent, reduces production costs, the advantage of environmental contamination reduction.
Embodiment
Below by embodiment the present invention is described in further detail, but embodiment is not limited to the technical solution.
Embodiment 1:
Get fresh radix aconiti agrestis piece root 10kg, clean with clear water, add 20L 0.1mol/L H
2SO
4After the aqueous solution soaking 24 hours, put into refiner, add again 100L 0.1mol/L H
2SO
410min is extracted in aqueous solution homogenate, filters, and collects filtrate.Leftover materials add the 0.1mol/L H of 100L again
2SO
4The aqueous solution, under negative pressure 0.06MPa, cavitation DL liquid-solid extraction 30min filters, and this step repeats 4 times, and merging filtrate is concentrated.Process weight is the 732 type Zeo-karbs of 20kg, uses first the water elution of 4 times of column volumes, uses 70% ethanolic soln (containing 2%NaOH) wash-out again, collects elutriant, transfers pH 7.00, and is concentrated, removes ethanol.Concentrated solution is the D101 type macroporous adsorbent resin of 3kg through weight, uses first the ethanol elution of 6 column volumes 20%, again with 10 column volume 60% ethanol elutions, collects elutriant, is evaporated to driedly, gets the bulleyaconitine A crude product.Get the dissolve with ethanol solution of the ratio adding 65% of bulleyaconitine A crude product take solid-liquid ratio as 1:10, fully dissolving in 50 ℃ of water-baths, filtered while hot, be cooled to room temperature, put under 4 ℃ of conditions, leave standstill 24h, produce crystallization, crystal gets the finished product with 65% ethanolic soln repetitive scrubbing.The rate of transform of bulleyaconitine A is 40.57%, and purity is 98.86%.
Embodiment 2:
Get fresh radix aconiti agrestis piece root 10kg, clean with clear water, add 40L 0.2mol/L HCl aqueous solution soaking after 24 hours, put into refiner, add again the homogenate of the 60L 0.2mol/L HCl aqueous solution and extract 15min, filter, collect filtrate.Leftover materials add the 0.2mol/LHCl aqueous solution of 60L again, and under negative pressure 0.1MPa, cavitation DL liquid-solid extraction 60min filters, and this step repeats 4 times, and merging filtrate is concentrated.Process weight is the 732 type Zeo-karbs of 30kg, uses first the water elution of 4 times of column volumes, uses 2% HCl aqueous solution wash-out again, collects elutriant, transfers pH 7.00, and is concentrated.Concentrated solution is the AB-8 type macroporous adsorbent resin of 3kg through weight, uses first the ethanol elution of 4 column volumes 30%, again with 7 column volume 70% ethanol elutions, collects elutriant, is evaporated to driedly, gets the bulleyaconitine A crude product.Get the dissolve with ethanol solution of the ratio adding 70% of bulleyaconitine A crude product take solid-liquid ratio as 1:15, fully dissolving in 40 ℃ of water-baths, filtered while hot, be cooled to room temperature, put under 4 ℃ of conditions, leave standstill 24h, produce crystallization, crystal gets the finished product with 70% ethanolic soln repetitive scrubbing.The rate of transform of bulleyaconitine A is 50.49%, and purity is 97.18%.
Embodiment 3:
Get fresh radix aconiti agrestis piece root 10kg, clean with clear water, add 30L 0.4mol/L HCl aqueous solution soaking after 24 hours, put into refiner, 20min is extracted in the 0.4mol/L HCl aqueous solution homogenate that adds again 80L, filters, and collects filtrate.Leftover materials add the 0.4mol/L HCl aqueous solution of 80L again, and under negative pressure 0.08MPa, cavitation DL liquid-solid extraction 45min filters.This step repeats 4 times, and merging filtrate is concentrated.Process weight is the 732 type Zeo-karbs of 20kg, uses first the water elution of 4 times of column volumes, uses the NaCl eluant solution of 3mol/L again, collects elutriant, and is concentrated.Concentrated solution is the D101 type macroporous adsorbent resin of 3kg through weight, uses first the ethanol elution of 3 column volumes 40%, again with 5 column volume 80% ethanol elutions, collects elutriant, is evaporated to driedly, gets the bulleyaconitine A crude product.Get the dissolve with ethanol solution of the ratio adding 80% of bulleyaconitine A crude product take solid-liquid ratio as 1:20, fully dissolving in 60 ℃ of water-baths, filtered while hot, be cooled to room temperature, put under 4 ℃ of conditions, leave standstill 24h, produce crystallization, crystal gets the finished product with 80% ethanolic soln repetitive scrubbing.The rate of transform of bulleyaconitine A is 45.81%, and purity is 98.61%.
Claims (5)
1. the preparation method of a high-purity bulleyaconitine A may further comprise the steps:
(1) get fresh radix aconiti agrestis piece root, clean with clear water first, press the solid-liquid ratio immersion radix aconiti agrestis 24 hours of 1:2～1:4 with aqueous acid again, described aqueous acid is HCl or the H of concentration 0.1mol/L～0.4mol/L
2SO
4The aqueous solution;
(2) soaked radix aconiti agrestis piece root is put into refiner, add described aqueous acid by the solid-liquid ratio of 1:6～1:10,10～20min is extracted in homogenate, filters afterwards, and collects filtrate;
(3) material after homogenate is extracted is pressed 1:6～1:10 solid-liquid ratio again and is added aqueous acid, and cavitation DL liquid-solid extraction 4 times extracts 30～60min at every turn, filters and collect filtrate;
(4) merge twice filtrate, concentrated, behind ion exchange resin column chromatography and macroporous adsorbent resin column chromatography gradient elution, get respectively again the bulleyaconitine A crude product;
(5) solid-liquid ratio by 1:10～1:20 mixes bulleyaconitine A crude product and aqueous ethanolic solution, and the volume fraction 65%～80% of aqueous ethanolic solution is bathed dissolving at 40 ℃～60 ℃ Water Unders; Filter, filtrate is cooled to place under 4 ℃ of conditions after the room temperature again leaves standstill crystallization, and crystal aqueous ethanolic solution repetitive scrubbing gets the finished product.
2. the preparation method of high-purity bulleyaconitine A according to claim 1, it is characterized in that: the described cavitation DL of step (3) liquid-solid extraction carries out under negative pressure 0.06～0.1MPa suction condition.
3. the preparation method of high-purity bulleyaconitine A according to claim 1, it is characterized in that: filter cloth is all adopted in the filtration described in each step, throttling component 0.02～10 μ m particle, adopt negative pressure 0.06～0.1MPa suction filtration, rotor stirs with the speed of rotating speed 1800-2400r/min simultaneously, stops up to prevent precipitation.
4. the preparation method of high-purity bulleyaconitine A according to claim 1, it is characterized in that: the employed sorbent material of the described column chromatography of step (4) is Zeo-karb and polystyrene type macroporous adsorbent resin.
5. the preparation method of high-purity bulleyaconitine A according to claim 4, it is characterized in that: the eluent of described Zeo-karb is a kind of of NaCl solution, HCl solution, alkaline ethanol solution or ammonia soln; The eluent of polystyrene type macroporous adsorbent resin is water or aqueous ethanolic solution.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104326981A (en) * | 2014-10-16 | 2015-02-04 | 云南大围山生物制药有限公司 | Bulleyaconitine A efficient extraction and separation method |
| CN109734664A (en) * | 2019-03-15 | 2019-05-10 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A form D and the preparation method and application thereof |
| CN109776417A (en) * | 2019-03-15 | 2019-05-21 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A G crystal form and the preparation method and application thereof |
| CN109776416A (en) * | 2019-03-15 | 2019-05-21 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A C crystal form and the preparation method and application thereof |
| CN109824595A (en) * | 2019-03-15 | 2019-05-31 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A crystal form E and the preparation method and application thereof |
| CN111875541A (en) * | 2020-07-03 | 2020-11-03 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polymorphism, preparation method and application thereof |
| CN115703740A (en) * | 2021-08-17 | 2023-02-17 | 昆药集团股份有限公司 | Preparation method of bulleyaconitine A |
| CN117327013A (en) * | 2023-12-01 | 2024-01-02 | 云南省药物研究所 | Preparation method of bulleyaconitine A |
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| CN109776416A (en) * | 2019-03-15 | 2019-05-21 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A C crystal form and the preparation method and application thereof |
| CN109824595A (en) * | 2019-03-15 | 2019-05-31 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A crystal form E and the preparation method and application thereof |
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| CN109734664A (en) * | 2019-03-15 | 2019-05-10 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A form D and the preparation method and application thereof |
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| CN109776417A (en) * | 2019-03-15 | 2019-05-21 | 云南昊邦制药有限公司 | A kind of bulleyaconitine A G crystal form and the preparation method and application thereof |
| JP2022525120A (en) * | 2019-03-15 | 2022-05-11 | ユンナン ハオピィ ファーマシューティカルズ エルティーディー | D crystal form of braiaconitine A and its production method and use |
| CN111875541A (en) * | 2020-07-03 | 2020-11-03 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polymorphism, preparation method and application thereof |
| CN115650917A (en) * | 2020-07-03 | 2023-01-31 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polycrystalline type and preparation method and application thereof |
| CN115703740A (en) * | 2021-08-17 | 2023-02-17 | 昆药集团股份有限公司 | Preparation method of bulleyaconitine A |
| CN117327013A (en) * | 2023-12-01 | 2024-01-02 | 云南省药物研究所 | Preparation method of bulleyaconitine A |
| CN117327013B (en) * | 2023-12-01 | 2024-02-02 | 云南省药物研究所 | Preparation method of bulleyaconitine A |
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