CN101264443B - Preparation of adsorption resin with hydrophobic and dipolar synergism and application in purifying total alkaloids of periwinkle - Google Patents
Preparation of adsorption resin with hydrophobic and dipolar synergism and application in purifying total alkaloids of periwinkle Download PDFInfo
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- CN101264443B CN101264443B CN2008100528784A CN200810052878A CN101264443B CN 101264443 B CN101264443 B CN 101264443B CN 2008100528784 A CN2008100528784 A CN 2008100528784A CN 200810052878 A CN200810052878 A CN 200810052878A CN 101264443 B CN101264443 B CN 101264443B
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Abstract
The invention discloses a preparation method of adsorption resin with the properties of hydrophobic interaction and dipole synergistic effect and an application thereof in the purification of periwinkle total alkaloid. The preparation method comprises the following steps: (1) polyvinyl alcohol is dissolved in the water to obtain aqueous phase solution, (2) methacrylate and divinylbenzene are made monomer of polymerization reaction, and toluene and long chain alkane with mass ratio 2:1 are adopted as mixed pore-foaming agent, azobisisobutyronitrile is adopted as the initiator, and oil phase is made, (3) the aqueous phase and the oil phase are mixed together with the volume ratio 3:1 and heated, and the adsorption resin is acquired by polymerization reaction, and (4) the adsorption resin is arranged in the adsorption column, the periwinkle grass powder is dissolved in the sulfate aqueous solution, the acquired clear water solution is absorbed by the adsorption column and eluted by ethanol-water solution step by step, the impurity is removed by ethanol aqueous solution of low concentration, and the solid periwinkle total alkaloid with percentage mass content 15 to 30% is acquired through elution by ethanol aqueous solution of high concentration. The adsorption resin has the advantages of simple technology, no use of toxic organic solvent, and low investment cost, thus being suitable for industrialized mass production.
Description
[technical field]:
The extracting method of the extraction and the separation technology field, particularly catharanthus roseus total alkaloids of pharmaceutically active ingredient in the present invention relates to reaches the preparation of employed polymeric adsorbent in this method.
[background technology]:
Catharanthus roseus (Catharanthus roseus L.) is an Apocynaceae Vinca plant.Originate in Africa, China Hainan, Guizhou one have cultivation.Catharanthus roseus often is used to treat malaria, diarrhoea, diabetes, hypertension, skin disease and Hodgkin's disease as a kind of traditional medicinal plant among the people.Recent studies shows, contains multiple alkaloid in the catharanthus roseus, and part biological alkali has tangible antitumor activity, thereby catharanthus roseus becomes important anticancer plants resource both at home and abroad.
Vincaleukoblastinum (vinblastine) is a kind of dimeric indole Alkaloid with tangible antitumor activity that extracts from catharanthus roseus.It has significant curative effect to Hodgkin's disease and non-cellule type tumour, malignant lymphatic tumor etc.Year was still one of main antitumor medication so far surplus its sulfate had been widely used in clinical 30.
Catharanthine (cathearanthine) has certain hypoglycemic activity, and vindoline (vindoline) has the effect of analgesia and diuresis.What is more important catharanthine and vindoline are the precursors of synthetic vincaleukoblastinum.
The molecular structure of vincaleukoblastinum, catharanthine and vindoline is as follows:
The molecular structure of molecular structural formula 3 vindolines of formula 1 vincaleukoblastinum
Catharanthus roseus total alkaloids is the general name of indoles alkaloid important in the catharanthus roseus, comprises that mainly vincaleukoblastinum, catharanthine and vindoline etc. have the alkaloid of significant medical value.At present, the acquisition of catharanthus roseus total alkaloids mainly is to extract from the catharanthus roseus plant.Yet catharanthus roseus total alkaloids content in catharanthus roseus is extremely low, and other dopant species is many, quantity is big in the catharanthus roseus plant, structure is unknown, and the extracting method of therefore setting up a kind of efficient, simple and direct catharanthus roseus total alkaloids seems particularly important.
Existing extraction about catharanthus roseus total alkaloids mainly contains solvent extraction method and column chromatography.[Li Xiaolei, let alone dragon etc., 2004 the 35th the 4th phases of volume of the extraction purifying of antineoplastic vincaleukoblastinum and the research overview Chinese Journal of Pharmaceuticals of analytical method] wherein, the solvent extraction complex steps, consume a large amount of solvents, the column chromatography rule is used organic solvent wash-outs such as benzene, benzinum, chloroform more, and products obtained therefrom purity is not high, preparation amount is little, is not suitable for enlarging producing.
[summary of the invention]:
The objective of the invention is to solve in the existing catharanthus roseus total alkaloids extractive technique and have the cost height, consume the problem of a large amount of organic solvents, provide a kind of adsorbent resin preparation method thereof that has hydrophobic and dipolar synergism concurrently to reach in the catharanthus roseus total alkaloids Application in Purification.
The present invention is according to the content characteristics of catharanthus roseus total alkaloids in the catharanthus roseus plant and other impurity, utilize alkaloid different with polarity between impurity, synthesized a kind of hydrophobic and polymeric adsorbent dipolar synergism of having concurrently, ratio by hydrophobic part in the regulation and control resin matrix and low pole part, make polymeric adsorbent to vincaleukoblastinum, catharanthine, embody stronger selectivity on vindoline and the adsorption capacity to other impurity in the catharanthus roseus, thereby utilize the method for gradient elution, only through the technological process in a step " absorption-wash-out ", can remove impurity, preparation high-purity catharanthus roseus total alkaloids.
The preparation method who has the polymeric adsorbent of hydrophobic effect and dipole effect concurrently provided by the invention, realize by following steps:
The first, under the normal temperature, polyethylene of dispersing agent alcohol is dissolved in the water, is made into the water that mass concentration is 0.5%-2%;
The second, the monomer of forming polymerisation by methyl acrylate and divinylbenzene mutually, wherein the mass fraction of methyl acrylate is 30～50% of a monomer phase gross mass, surplus is a divinylbenzene; Toluene and the long chain alkane getting mass ratio simultaneously and be 2: 1 make to mix pore-foaming agent, the pore-foaming agent total amount is 100%～150% of a monomer phase gross mass, make initator with azodiisobutyronitrile, its consumption is 1～3% of a monomer phase gross mass, is made into oil phase after said components is mixed;
Three, before the reaction beginning, earlier water is poured in the there-necked flask, and after being heated to 30-50 ℃, oil phase is added in the there-necked flask, the volume ratio of water and oil phase is 3: 1; Start stirring, regulate mixing speed from slow to fast, behind 0.3-1.0mm, begin to heat up to droplet size, to 60-80 ℃ of reaction 2-6 hour, continue to be warming up to 85 ℃ of reactions 6 hours more earlier, stop reaction, leave standstill to room temperature, at last after filtration, carrying out washing treatment obtains required polymeric adsorbent.
The application of the polymeric adsorbent of method for preparing is used for from catharanthus roseus complete stool preparation high-purity catharanthus roseus total alkaloids, and concrete steps are as follows:
The first step, the catharanthus roseus grass meal is dissolved in the aqueous sulfuric acid of 0.5%-1.5%, wherein the mass ratio of catharanthus roseus grass meal and aqueous sulfuric acid is 1: 3-1: 7,60 ℃ were refluxed 2～3 hours, and repeated to extract 2-3 time;
Second goes on foot, said extracted liquid is filtered, and the centrifugal clear aqueous solution that obtains is made upper prop liquid with this clear aqueous solution;
The 3rd step, the polymeric adsorbent of method for preparing is packed in the adsorption column, the adsorption column diameter is 1 with the column length ratio: 5-1: 20; Under the room temperature, with upper prop liquid with 0.5～1.5BV/ hour flow velocity by the resin adsorption post;
The 4th step, washed resin adsorption column are to flowing out liquid for neutral, be 40～50% with volumn concentration respectively, 70～80% ethanol-water solution stepwise elution, eluent decompression, concentrate drying with 70～80% promptly get highly purified catharanthus roseus total alkaloids (comprising vincaleukoblastinum, catharanthine and vindoline).
The quality percentage composition of catharanthus roseus total alkaloids reaches 15～30% in the solid that above drying makes.
Advantage of the present invention and good effect:
The present invention is according to vincaleukoblastinum, the architectural feature of catharanthine and vindoline, utilize catharanthus roseus total alkaloids in the catharanthus roseus plant different with polarity between impurity, synthesized a kind of macroporous absorbent resin that has hydrophobic effect and dipole effect concurrently, this resin has still kept the rigid backbone of traditional macroporous absorbent resin, thereby good working strength arranged, regulate and control hydrophobic effect and dipole effect in the resin matrix simultaneously, synergy by resin hydrophobic and dipole in adsorption process, improved polymeric adsorbent to vincaleukoblastinum, catharanthine, the adsorptive selectivity of vindoline and other impurity, thus utilize the ethanol aqueous wash of low concentration to remove decontamination, the ethanol water wash-out of high concentration obtains catharanthus roseus total alkaloids.The present invention is a raw material with the catharanthus roseus herb, with the sour water is to extract solvent, only by " adsorption-desorption " step simple process, can separation and purification obtain highly purified catharanthus roseus total alkaloids extract from the catharanthus roseus extract.Vincaleukoblastinum, catharanthine and three kinds of alkaloidal total contents of vindoline can reach 15～30% in the product.Technology of the present invention is simple, does not use toxic organic solvent, and cost of investment is low, is easy to the big generation of industrialization.
[specific embodiment]:
The preparation of embodiment 1, polymeric adsorbent
At normal temperatures, polyvinyl alcohol is dissolved in the water, is made into mass fraction and is 0.5% aqueous solution 450g, water-bath is heated to 40 ℃ in the 1000ml there-necked flask; Mixture with 24g methyl acrylate and 36g divinylbenzene is the overall reaction monomer, make to mix pore-foaming agent with the mixture of 60g toluene and 30g long chain alkane, with the 0.60g azodiisobutyronitrile is initator, mixing the back adds in the there-necked flask, begin to stir, regulate the oil droplet size between 0.3-1.0mm, through suspension polymerisation, programming rate with 1 ℃/min slowly is warming up to 70 ℃ of reactions 4 hours, continue to be warming up to 85 ℃ of reactions 6 hours again, stop reaction, leave standstill to room temperature, after filtration, after the carrying out washing treatment, prepare required polymeric adsorbent.
Embodiment 2
At normal temperatures, polyvinyl alcohol is dissolved in the water, is made into mass fraction and is 1% aqueous solution 450g, water-bath is heated to 40 ℃ in the 1000ml there-necked flask; Mixture with 30g methyl acrylate and 45g divinylbenzene is the overall reaction monomer, make to mix perforating agent with the mixture of 50g toluene and 25g long chain alkane, with the 0.85g azodiisobutyronitrile is initator, mixing the back adds in the there-necked flask, begin to stir, regulate the oil droplet size between 0.3-1.0mm, through suspension polymerisation, programming rate with 1 ℃/min slowly is warming up to 70 ℃ of reactions 4 hours, continue to be warming up to 85 ℃ of reactions 6 hours again, stop reaction, leave standstill to room temperature, after filtration, after the carrying out washing treatment, prepare required polymeric adsorbent.
Embodiment 3
At normal temperatures, polyvinyl alcohol is dissolved in the water, is made into mass fraction and is 1.5% aqueous solution 4.5kg, water-bath is heated to 40 ℃ in the 10L there-necked flask; Mixture with 0.35kg methyl acrylate and 0.35kg divinylbenzene is the overall reaction monomer, mixture with 0.50kg toluene and 0.25kg liquid wax is done the mixing perforating agent, with the 0.008kg azodiisobutyronitrile is initator, mixing the back adds in the there-necked flask, begin to stir, regulate the oil droplet size between 0.3-1.0mm, through suspension polymerisation, programming rate with 1 ℃/min slowly is warming up to 70 ℃ of reactions 4 hours, continue to be warming up to 85 ℃ of reactions 6 hours again, stop reaction, leave standstill to room temperature, after filtration, after the carrying out washing treatment, prepare required polymeric adsorbent.
The application of embodiment 4, polymeric adsorbent
Get 20g catharanthus roseus grass meal, the aqueous sulfuric acid that is dissolved in 100ml 1% added hot reflux 2 hours for 60 ℃, extract through centrifugal, filter clear aqueous solution.The aqueous solution that obtains is fed resin column (the column length 30cm that above-mentioned polymeric adsorbent is housed, internal diameter 18mm, wet resin 40ml is housed), adsorption rate 1BV/h is after absorption is finished, be washed to neutrality, successively with 40% (v/v) and 80% (v/v) ethanol water wash-out, flow velocity 0.5BV/h, the desorbed solution when collecting 80% ethanol elution, decompression distillation, vacuum drying promptly get solid extract.Detect through the Waters484 high performance liquid chromatograph, the purity of catharanthus roseus total alkaloids can reach 24.5%.
Embodiment 5
Get 50g catharanthus roseus grass meal, the aqueous sulfuric acid that is dissolved in 200ml 0.5% added hot reflux 3 hours for 60 ℃, extract through centrifugal, filter clear aqueous solution.The aqueous solution that obtains is fed resin column (the column length 30cm that above-mentioned resin is housed, internal diameter 18mm, wet resin 40ml is housed), adsorption rate 0.5BV/h is after absorption is finished, be washed to neutrality, successively with 40% (v/v) and 80% (v/v) ethanol water wash-out, flow velocity 0.5BV/h, the desorbed solution when collecting 80% ethanol elution, decompression distillation, vacuum drying promptly get solid extract.Detect through the Waters484 high performance liquid chromatograph, the purity of catharanthus roseus class TA can reach 25.2%.
Embodiment 6
Get 250g catharanthus roseus grass meal, the aqueous sulfuric acid that is dissolved in 1000ml 1.5% added hot reflux 2 hours for 60 ℃, extract through centrifugal, filter clear aqueous solution.The aqueous solution that obtains is fed resin column (the column length 40cm that above-mentioned resin is housed, internal diameter 40mm, wet resin 400ml is housed), adsorption rate 1BV/h is after absorption is finished, be washed to neutrality, successively with 40% (v/v) and 80% (v/v) ethanol water wash-out, flow velocity 0.5BV/h, the desorbed solution when collecting 80% ethanol elution, decompression distillation, vacuum drying promptly get solid extract.Detect through the Waters484 high performance liquid chromatograph, the purity of catharanthus roseus class TA can reach 25.3%.
Embodiment 7
Get 350g catharanthus roseus grass meal, the aqueous sulfuric acid that is dissolved in 1500ml 1% added hot reflux 2 hours for 60 ℃, extract through centrifugal, filter clear aqueous solution.The aqueous solution that obtains is fed resin column (the column length 40cm that above-mentioned resin is housed, internal diameter 40mm, wet resin 400ml is housed), adsorption rate 1.5BV/h is after absorption is finished, be washed to neutrality, successively with 40% (v/v) and 80% (v/v) ethanol water wash-out, flow velocity 0.5BV/h, the desorbed solution when collecting 80% ethanol elution, decompression distillation, vacuum drying promptly get solid extract.Detect through the Waters484 high performance liquid chromatograph, the purity of catharanthus roseus class TA can reach 24.8%.
Claims (2)
1. application that has the polymeric adsorbent of hydrophobic effect and dipole effect concurrently is used for from catharanthus roseus complete stool preparation high-purity catharanthus roseus total alkaloids, and concrete steps are as follows:
The first step, the catharanthus roseus grass meal is dissolved in the aqueous sulfuric acid of 0.5%-1.5%, wherein the mass ratio of catharanthus roseus grass meal and aqueous sulfuric acid is 1: 3-1: 7,60 ℃ were refluxed 2～3 hours, and repeated to extract 2-3 time;
Second goes on foot, said extracted liquid is filtered, and the centrifugal clear aqueous solution that obtains is made upper prop liquid with this clear aqueous solution;
The 3rd step, the polymeric adsorbent that will have hydrophobic effect and dipole effect concurrently are packed in the adsorption column, and the adsorption column diameter is 1 with the column length ratio: 5-1: 20; Under the room temperature, with upper prop liquid with 0.5～1.5BV/ hour flow velocity by the resin adsorption post;
The 4th step, washed resin adsorption column are to flowing out liquid for neutral, be 40～50% with volumn concentration respectively, 70～80% ethanol-water solution stepwise elution will promptly get highly purified catharanthus roseus total alkaloids through solution decompression, the concentrate drying that obtains behind 70～80% the ethanol-water solution wash-out;
Wherein, the preparation method of the described polymeric adsorbent that has hydrophobic effect and dipole effect concurrently of the 3rd step is as follows:
1), under the normal temperature, polyethylene of dispersing agent alcohol is dissolved in the water, is made into the water that mass concentration is 0.5%-2%;
2), the monomer of forming polymerisation by methyl acrylate and divinylbenzene mutually, wherein the mass fraction of methyl acrylate is 30～50% of a monomer phase gross mass, surplus is a divinylbenzene; Toluene and the long chain alkane getting mass ratio simultaneously and be 2: 1 make to mix pore-foaming agent, the pore-foaming agent total amount is 100%～150% of a monomer phase gross mass, make initator with azodiisobutyronitrile, its consumption is 1～3% of a monomer phase gross mass, is made into oil phase after said components is mixed;
3), before the reaction beginning, earlier water is poured in the there-necked flask, and after being heated to 30-50 ℃, oil phase is added in the there-necked flask, the volume ratio of water and oil phase is 3: 1; Start stirring, regulate mixing speed from slow to fast, behind 0.3-1.0mm, begin to heat up to droplet size, to 60-80 ℃ of reaction 2-6 hour, continue to be warming up to 85 ℃ of reactions 6 hours more earlier, stop reaction, leave standstill to room temperature, at last after filtration, carrying out washing treatment obtains required polymeric adsorbent.
2. application according to claim 1 is characterized in that the quality percentage composition of catharanthus roseus total alkaloids in the solid that drying makes reaches 15～30%.
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