CN101967151A - Preparation method for natural product podophyllotoxin - Google Patents
Preparation method for natural product podophyllotoxin Download PDFInfo
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- CN101967151A CN101967151A CN2010102107429A CN201010210742A CN101967151A CN 101967151 A CN101967151 A CN 101967151A CN 2010102107429 A CN2010102107429 A CN 2010102107429A CN 201010210742 A CN201010210742 A CN 201010210742A CN 101967151 A CN101967151 A CN 101967151A
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- podophyllotoxin
- chloroform
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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Abstract
The invention relates to a preparation method for natural product podophyllotoxin, which comprises the following steps of pulverizing raw materials into 20 to 60 meshes; taking CO2 and chloroform as solvents; super-critically extracting for 1 to 3 hours; washing analytic matters by utilizing deionized water; dissolving by utilizing chloroform; carrying out a medium-pressure alumina column chromatography; carrying out gradient elution by utilizing a petroleum ether-methanol chloroform mixing solution; collecting high-concentration fraction, concentrating and crystallizing; and recrystallizing the methanol chloroform mixing solution. The method for producing the podophyllotoxin has the advantages of less pollution, high extraction efficiency and less usage of organic solvents.
Description
Technical field:
The present invention relates to a kind of preparation method of natural product podophyllotoxin, especially a kind of employing supercritical CO
2Abstraction technique extraction and middle pressure alumina column chromatography prepare the method for podophyllotoxin.
Background technology:
The principle of supercritical carbon dioxide extraction sepn process is to utilize supercritical co that some special natural product is had special solvency action, utilize the dissolving power of supercritical co and the relation of its density, promptly utilize pressure and the influence of supercritical co dissolving power is carried out.Under supercritical state, supercritical co is contacted with material to be separated, it is extracted the composition of polarity size, boiling point height and molecular weight size selectively successively.Certainly, the resulting extract of corresponding each pressure range can not be single, but the mixing element that can control condition obtains optimum proportion, method by decompression, intensification makes supercutical fluid become common gases then, be extracted material and then separate out fully or substantially, separate the purpose of purifying thereby reach.It is the existing relatively extracting method of environmental protection.
Podophyllotoxin
Chemical name: 5R-5,8,8a, 9-tetrahydrochysene-9-hydroxyl-5-(3,4, the 5-2,4,5-trimethoxyphenyl) furans (3 ', 4 ': 6,7) naphtho--[2,3-d]-1, dioxane alkene-6 (5aH)-ketone between 3-.
Molecular weight: 414.41
Physical properties: white, needle-shaped crystals powder.Be soluble in chloroform, acetone, ethyl acetate and benzene, dissolve in ethanol, ether.
Podophyllotoxin is applied to the treatment of pointed condyloma, multiple shallow epitheliomatosis, anterior epithelium cornea knurl keratosis, childhood papilloma of larynx, wart (verruca vulgaris, verruca filiformis).Podophyllotoxin can effectively suppress simplexvirus, suppresses the cell mitotic division in mid-term, is used for viral venereal disease.98% above podophyllotoxin is made 0.5% tincture, and to be used for pointed condyloma evident in efficacy.
Podophyllotoxin belongs to ring xylogen lactone in the lignin, and mostly existing extracting method is traditional technology, and the organic reagent consumption is big, and is seriously polluted, and technical process has: ethanol or methanol extraction concentrate the back extraction, method crystallization or column chromatography.Pertinent literature is as follows:
" the high-purity podophyllotoxin new preparation process " that Wen Puhong delivers (the 18th the 10th phase of volume of " becoming more meticulous " October calendar year 2001), document operational path is: be raw material with the Chinese podophyllum root, methyl alcohol is made solvent, 7 ℃ of refluxing extraction 3 times, each 2 gained medicinal extract dissolve 8 ℃ of reflux with benzene, filter, concentrate, place crystallization, get light yellow crude product.Use the anhydrous alcohol solution crude product, behind drawing together property carbon decoloring, be condensed into arborescens, suspend with benzene and dissolve, abandon and hit insolubles.Adopt two one step crystallizings, earlier make solvent with benzene, removing behind most impurity is solvent recrystallization with benzene-ethanol again, dries 2h for 1 ℃, promptly gets elaboration podophyllotoxin rope, and its massfraction＞96%, productive rate are 1.7%.
Su Wei etc. provide table " extraction of podophyllotoxin and HPLC analyze in the plant root of Common Sinopodophyllum " (" Chinese Journal of Pharmaceuticals "), the document adopts two kinds of methods, (1) chemical extraction method: get the root of Common Sinopodophyllum powder, with the diacolation extraction repeatedly of 95% ethanol, concentrated extracting solution, cold water precipitate the about 100g of root of Common Sinopodophyllum resin (productive rate 10%).With the 100g resin with chloroform dissolving, filter, steam and remove solid part dissolve with ethanol behind the chloroform, add equal-volume benzene, the placement partial crystallization goes out, yield is about 20%, HPLC purity assay about 80%.(2) column chromatography for separation and purifying: chromatography neutral alumina (100～200 order) dry column-packing.Get crude product 20g, add dehydrated alcohol 40ml dissolving back tripping small amounts aluminium, the room temperature volatilization adds to capital behind the ethanol to the greatest extent, binds with small amounts aluminium.With ethanol-benzole soln is the moving phase wash-out.Collect the every stream of elutriant part 50ml, total 1000ml evaporate to dryness is dissolved in ethanol 100ml with it, filters, and adds benzene 100ml, and jolting frequently, is placed with crystallization and separates out, and crystalline substance is assembled in filter behind the 12h, and benzene is washed, and repeats crystallization 3 times.Behind the drying under reduced pressure white crystalline powder 14g, productive rate is about 80%, total recovery about 1.4%.
Patent (application number ZL200410052833.9) " a kind of improvement technology for preparing podophyllotoxin from Chinese podophyllum root ", the technology that this patent adopts are solvent crystallization and decompression column chromatography.
Patent (application number 200910047696.2) " a kind of method for preparing high-purity podophyllotoxin from Chinese podophyllum root ", this patent operational path is alcohols extraction-extraction-high-pressure column chromatography.
Summary of the invention:
The technical problem to be solved in the present invention provides a kind of novel preparation method of podophyllotoxin.This method adopts supercritical extraction, can improve the yield of podophyllotoxin, reduces purification step, reduces the toxic agent consumption.
In order to solve the problems of the technologies described above, extractive technique scheme of the present invention is as follows:
A kind of preparation method of natural product podophyllotoxin is characterized in that comprising following steps:
1) supercritical CO
2Extraction: with Berberidaceae plant Chinese podophyllum root rhizome impurity elimination drying and crushing 40-80 order, drop in the extraction kettle, the debugging extraction kettle, separating still, warming apparatus and refrigeration plant works better are opened compression pump and are pressurised into 41-43MPa, pumping liquid CO
2Extract podophyllotoxin with the chloroform entrainment agent, from separating still, resolve extract, get the podophyllotoxin crude product;
2) press alumina column chromatography in: above-mentioned podophyllotoxin crude product is doubly measured deionized water backflow dissolving with 3-6, abandon water layer, add the chloroform dissolving, filter in the adding and press alumina column, sherwood oil-methyl alcohol chloroform gradient elution, the high density flow point is collected in the liquid phase monitoring, be concentrated into original volume 1/3-1/5, the refrigeration crystallization;
3) recrystallization: leach above-mentioned crystallisate, reflux with chloroform and dissolve, add the 1/3-1/4 methanol crystallization of its volume again, be drying to obtain the podophyllotoxin product.
Described step 1) supercritical CO
2Extraction conditions: CO
2Flow control is 28-35kg/h, and entrainment agent consumption 1-2% extracts 35-4 ℃ of temperature, and 1-3 hour dynamic extraction time, parsing pressure is 8-10MPa, resolution temperature 45-5 ℃.
Described step 2) press the alumina column chromatography condition in: aluminum oxide is a 200-300 purpose neutral alumina, internal diameter 100-200mm, and post blade diameter length ratio 1: 15, pressure-controlling is at 0.6-1.0MPa,
Described step 2) gradient elution is: sherwood oil consumption 10-20BV, methyl alcohol chloroform ratio 2: 5.
There is following advantage in the present invention:
1) present method adopts CO
2Supercritical extraction, the extraction efficiency height, extract impurity is few, pollutes few.
2) press alumina column in, processing speed is fast, and the wet method upper prop is simple to operate.
3) solvent species is few, and it is easier to store recovery.
Further specify the present invention below in conjunction with embodiment, but the scope of protection of present invention is not limited to following embodiment.
Embodiment:
Embodiment 1:
Get the Chinese podophyllum root raw material, select the impurity elimination drying, pulverize 60 orders, weighing 2kg, the extraction kettle of packing into, sealing will be extracted temperature and be transferred to 35 ℃, and the knockout tower temperature transfers to 45 ℃, extracts pressure 41MPa, and parsing pressure is 8MPa, CO
2Gas is emitted from steel cylinder, through behind the gas purifier in liquefied pot, liquefaction, enter storage tank and 1% chloroform entrainment agent is pumped into cleaner with high pressure measurement, to assigned temperature and pressure,, open relief valve by preheater with flow velocity 35kg/h, by relief valve control above-mentioned parameter, dynamic extraction 2 hours.Emit extract after the shutdown; collecting extract washs 3 times with the backflow of 3 times of amount deionized waters; extract dissolves with chloroform again; add to filter and press alumina column in pumping into (aluminum oxide is a 200-300 order neutral alumina; internal diameter 100mm; the high 1.5m of post), earlier with 20BV sherwood oil wash-out impurity, 2: 5 wash-out flow points of methyl alcohol chloroform ratio; pressure-controlling is at 0.6-1.0MPa; the high density flow point is collected in the liquid phase monitoring, is concentrated into original volume 1/3; the refrigeration crystallization; be placed in 0 ℃ of environment, crystallization 24 hours leaches the imitative dissolving of crystallisate chlorine backflow; 1/4 methanol crystallization that adds its volume again; leach the crystal cryodrying and get podophyllotoxin, content 99%, yield 75% (in podophyllotoxin in the raw material).
Embodiment 2:
Get the Chinese podophyllum root raw material, select the impurity elimination drying, pulverize 40 orders, weighing 2kg, the extraction kettle of packing into, sealing will be extracted temperature and be transferred to 40 ℃, and the knockout tower temperature transfers to 50 ℃, extracts pressure 43MPa, and parsing pressure is 10MPa, CO
2Gas is emitted from steel cylinder, through behind the gas purifier in liquefied pot, liquefaction, enter storage tank and 2% chloroform entrainment agent is pumped into cleaner with high pressure measurement, to assigned temperature and pressure,, open relief valve by preheater with flow velocity 28kg/h, by relief valve control above-mentioned parameter, dynamic extraction 3 hours.Emit extract after the shutdown; collecting extract washs 2 times with the backflow of 6 times of amount deionized waters; extract dissolves with chloroform again; (aluminum oxide is a 200-300 order neutral alumina to press alumina column during filtration pumps into; internal diameter 100mm; the high 1.5m of post), earlier with 15BV sherwood oil wash-out impurity, 2: 5 wash-out flow points of methyl alcohol chloroform ratio; pressure-controlling is at 0.6-1.0MPa; the high density flow point is collected in the liquid phase monitoring, is concentrated into original volume 1/5; the refrigeration crystallization; be placed in 0 ℃ of environment, crystallization 36 hours leaches the imitative dissolving of crystallisate chlorine backflow; 1/3 methanol crystallization that adds its volume again; leach the crystal cryodrying and get podophyllotoxin, content 98.5%, yield 74% (in podophyllotoxin in the raw material).
Embodiment 3:
Get the Chinese podophyllum root raw material, select the impurity elimination drying, pulverize 60 orders, weighing 2kg, the extraction kettle of packing into, sealing will be extracted temperature and be transferred to 45 ℃, and the knockout tower temperature transfers to 4 ℃, extracts pressure 42MPa, and parsing pressure is 10MPa, CO
2Gas is emitted from steel cylinder, through behind the gas purifier in liquefied pot, liquefaction, enter storage tank and 1% chloroform entrainment agent is pumped into cleaner with high pressure measurement, to assigned temperature and pressure,, open relief valve by preheater with flow velocity 32kg/h, by relief valve control above-mentioned parameter, dynamic extraction 3 hours.Emit extract after the shutdown; collecting extract washs 3 times with the backflow of 5 times of amount deionized waters; extract dissolves with chloroform again; (aluminum oxide is a 200-300 order neutral alumina to press alumina column during adding filters and adds; internal diameter 100mm; the high 1.5m of post), earlier with 10V sherwood oil wash-out impurity, 2: 5 wash-out flow points of methyl alcohol chloroform ratio; pressure-controlling is at 0.6-1.0MPa; the high density flow point is collected in the liquid phase monitoring, is concentrated into original volume 1/3; the refrigeration crystallization; be placed in 0 ℃ of environment, crystallization 20 hours leaches the imitative dissolving of crystallisate chlorine backflow; 1/4 methanol crystallization that adds its volume again; leach the crystal cryodrying and get podophyllotoxin, content 99%, yield 70% (in podophyllotoxin in the raw material).
Embodiment 4:
Get the Chinese podophyllum root raw material, select the impurity elimination drying, pulverize 60 orders, weighing 4kg, the extraction kettle of packing into, sealing will be extracted temperature and be transferred to 3 ℃, and the knockout tower temperature transfers to 4 ℃, extracts pressure 42MPa, and parsing pressure is 8MPa, CO
2Gas is emitted from steel cylinder, through behind the gas purifier in liquefied pot, liquefaction, enter storage tank and 2% chloroform entrainment agent is pumped into cleaner with high pressure measurement, to assigned temperature and pressure,, open relief valve by preheater with flow velocity 30kg/h, by relief valve control above-mentioned parameter, dynamic extraction 3 hours.Emit extract after the shutdown; collecting extract washs 3 times with the backflow of 5 times of amount deionized waters; extract dissolves with chloroform again; (aluminum oxide is a 200-300 order neutral alumina to press alumina column during adding filters and adds; internal diameter 200mm; the high 3m of post), earlier with 20BV sherwood oil wash-out impurity, 2: 5 wash-out flow points of methyl alcohol chloroform ratio; pressure-controlling is at 0.6-1.0MPa; the high density flow point is collected in the liquid phase monitoring, is concentrated into original volume 1/3; the refrigeration crystallization; be placed in 0 ℃ of environment, crystallization 30 hours leaches the imitative dissolving of crystallisate chlorine backflow; 1/3 methanol crystallization that adds its volume again; leach the crystal cryodrying and get podophyllotoxin, content 99%, yield 72% (in podophyllotoxin in the raw material).
Claims (5)
1. the preparation method of a natural product podophyllotoxin is characterized in that comprising following steps:
1) supercritical CO
2Extraction: with Berberidaceae plant Chinese podophyllum root rhizome impurity elimination drying and crushing 40-80 order, drop in the extraction kettle, the debugging extraction kettle, separating still, warming apparatus and refrigeration plant works better are opened compression pump and are pressurised into 41-43MPa, pumping liquid CO
2Extract podophyllotoxin with the chloroform entrainment agent, from separating still, resolve extract, get the podophyllotoxin crude product;
2) press alumina column chromatography in: above-mentioned podophyllotoxin crude product is doubly measured deionized water backflow dissolving with 3-6, abandon water layer, add the chloroform dissolving, filter in the adding and press alumina column, sherwood oil-methyl alcohol chloroform gradient elution, the high density flow point is collected in the liquid phase monitoring, be concentrated into original volume 1/3-1/5, the refrigeration crystallization;
3) recrystallization: leach above-mentioned crystallisate, reflux with chloroform and dissolve, add the 1/3-1/4 methanol crystallization of its volume again, be drying to obtain the podophyllotoxin product.
2. the preparation method of natural product podophyllotoxin according to claim 1 is characterized in that optional Chinese podophyllum root of described step 1) raw material or Dysosma versipellis.
3. the preparation method of natural product podophyllotoxin according to claim 1 is characterized in that described step 1) supercritical CO
2Extraction conditions: CO
2Flow control is 28-35kg/h, and entrainment agent consumption 1-2% extracts 35-40 ℃ of temperature, and 1-3 hour dynamic extraction time, parsing pressure is 8-10MPa, resolution temperature 45-50 ℃.
4. the preparation method of natural product podophyllotoxin according to claim 1, it is characterized in that described step 2) the middle alumina column chromatography condition of pressing: aluminum oxide is a 200-300 purpose neutral alumina, internal diameter 100-200mm, post blade diameter length ratio 1: 15, pressure-controlling is at 0.6-1.0MPa
5. the preparation method of natural product podophyllotoxin according to claim 1 is characterized in that described step 2) gradient elution is: sherwood oil consumption 10-20BV, methyl alcohol chloroform ratio 2: 5.
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| CN2010102107429A CN101967151A (en) | 2010-06-28 | 2010-06-28 | Preparation method for natural product podophyllotoxin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098583A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Podophyllotoxin crystal X material, preparation method, pharmaceutical composition and use |
| CN108098458A (en) * | 2017-08-09 | 2018-06-01 | 徐先顺 | A kind of two white prescription of ghost for anti-HPV6/11 |
| CN112125917A (en) * | 2020-11-04 | 2020-12-25 | 中国科学院西北高原生物研究所 | Extraction method of podophyllotoxin |
-
2010
- 2010-06-28 CN CN2010102107429A patent/CN101967151A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098583A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Podophyllotoxin crystal X material, preparation method, pharmaceutical composition and use |
| CN104098583B (en) * | 2013-04-09 | 2018-02-02 | 中国医学科学院药物研究所 | Podophyllotoxin crystalline substance X-type material and preparation method and its pharmaceutical composition and purposes |
| CN108098458A (en) * | 2017-08-09 | 2018-06-01 | 徐先顺 | A kind of two white prescription of ghost for anti-HPV6/11 |
| CN108098458B (en) * | 2017-08-09 | 2019-12-24 | 徐先顺 | Gel for resisting HPV6/11 |
| CN112125917A (en) * | 2020-11-04 | 2020-12-25 | 中国科学院西北高原生物研究所 | Extraction method of podophyllotoxin |
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Application publication date: 20110209 |