CN101531663A - Method for preparing methyl pheophorbide-A from water-blooming cyanobacteria - Google Patents
Method for preparing methyl pheophorbide-A from water-blooming cyanobacteria Download PDFInfo
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Abstract
The invention relates to a method for preparing methyl pheophorbide-A, which is characterized in that the water-blooming cyanobacteria is used as the raw material. The method comprises the following four steps of: (i) destroying the tissue of water-blooming cyanobacteria, (ii) extracting by organic solvent; (iii) methyl-esterifying the organic solvent extractive obtained in the above steps and gaining crude product; and (iv) purification. The invention can prepare and obtain methyl pheophorbide-A from water-blooming cyanobacteria of the fresh water by a simple method, and can solve the resource utilization problem in the treatment of the water-blooming cyanobacteria and provide gospel for the cancer patients.
Description
Technical field
The present invention relates to a kind ofly prepare the method for pheophorbide A methyl esters, belong to medicine, environmental technology field from bloom blue algae.
Background technology
The economic rapid deterioration that is accompanied by ecotope of advancing by leaps and bounds makes people's existence stand the intensive test.And a current very serious pollution embodiment is " green tide " and " red tide " in the seawater in the fresh water, and green tide is so-called blue-green alga bloom." wawter bloom " is frequent in recent years occurs, and area spreads year by year, and the time length prolongs year by year.Taihu Lake, Dian Chi, Chaohu, Hongchehu Lake have " wawter bloom ", even the mobile river, as " wawter bloom " also occurring in the section of river, Hankow, downstream, Han River, maximum tributary----, the Changjiang river.The maximum harm that " wawter bloom " causes in the fresh water is: the drinking water source is on the hazard, and the algae toxin influences human beings'health by food chain, and the secondary metabolite of blue-green algae " wawter bloom " can damage liver, has short cancer effect, directly threatens human beings'health and existence.In addition, the filtration unit of waterworks is by algae " wawter bloom " filling, and " wawter bloom " that swim on the water surface influences view, and unpleasant stink is arranged.
The blue-green alga bloom especially improvement of the blue-green alga bloom in the large-size lake is a global difficult problem.World many countries has been attempted many methods to the improvement of blue-green alga bloom, adopts machinery to remove algae, chemical algae removing, measures such as filter food control algae and aquatic vegetation recovery, obtained the effect of control blue-green alga bloom in short period of time, yet, spend one or two years and can breed appearance in a large number again.Blue-green algae is administered needs secular a large amount of inputs, has increased the weight of burden on society to a certain extent.In recent years, bloom blue algae is studied producing agriculture fertilizer and is used for agriculture production, also be studied to be used to extract some cheap industrial chemicals, as: gamma-linolenic acid etc.Yet the abundantest composition of content is a Chlorophyll A in the blue-green algae, if can be used the bigger value of creation.
Pheophorbide A is a kind of photosensitizers, can be used for by the photodynamic therapy for tumour, but have bigger phototoxicity.HPPH (2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a, promptly (2-[1-hexyloxy ethyl]-2-remove the burnt pheophorbide A of vinyl) is the analogue of pheophorbide A, it is the s-generation photosensitizers of U.S. ROSWELLPARK CANCERINSTITUTE development, studies show that it has the treatment characteristics that tumor effect is good, phototoxicity is little.HPPH is that methyl compound with pheophorbide A is a feedstock production, and its sources of initial raw materials is in a kind of marine algae plant Spirulinadestridratada, and plant resources is less, causes the HPPH production cost very high.
2-[1-is oxygen base ethyl]-2-removes the burnt pheophorbide A of vinyl
The present inventor has found to prepare pheophorbide A methyl esters from the bloom blue algae of fresh water for the first time.The present invention can prepare pheophorbide A methyl esters by easy method from the bloom blue algae of fresh water, not only can solve the problem of the utilization of resources in the improvement of blue-green alga bloom, and can reduce the production cost of novel photosensitive agent HPPH, for the cancer patients brings glad tidings.
Summary of the invention:
The invention provides the method that a kind of bloom blue algae from fresh water prepares pheophorbide A methyl esters, raw material sources are extensive, and method is easy, easy to operate, the pheophorbide A methyl esters purity height that obtains is fit to the big production demand of industry, has solved the bloom blue algae resource utilization issue simultaneously.
The invention provides a kind of method for preparing pheophorbide A methyl esters, it is characterized in that using bloom blue algae as raw material, described method comprises following four steps: (i) bloom blue algae is carried out disorganization, (ii) use organic solvent extraction, (iii) with the extractive with organic solvent esterification that obtains in the above-mentioned steps, obtain crude product, and (iv) purifying.
Pheophorbide A methyl esters structural formula is as follows:
Pheophorbide-a methyl esters
(Methyl?pheophorbide-a)
In the preferred embodiment of the invention, wherein said bloom blue algae is the Taihu Lake blue-green algae.
In the preferred embodiment of the invention, wherein said disorganization step is mechanical crushing method or freezing crushing method, and wherein said mechanical crushing method is for example used blue-green algae cut short and ground; The freezing crushing method is to add cryogenic liquid in blue-green algae, stir and destroy cell and tissue, wherein cryogenic liquid is selected from and can reaches-50 ℃ to-120 ℃ cryogenic liquid, the low-temperature solvent that low-temperature solvent that preferred liquid nitrogen, liquid nitrogen and organic solvent form or dry ice and organic solvent form, wherein said organic solvent is selected from C3-C6 ketone, the pure and mild C4-C6 ether of C1-C4 low alkyl group, preferred acetone, methyl alcohol, ethanol and ether, more preferably acetone.
In the preferred embodiment of the invention, wherein said organic solvent extraction step is to add organic solvent in the sample after historrhexis, carrying out one or many by immersion or reflux type extracts, the organic solvent that adopts when wherein extracting is selected from C3-C6 ketone, C4-C6 ether, the C1-C4 lower alkyl alcohol, the C1-C2 halogenated alkane, and the mixed solvent of above-mentioned solvent and water or C5-C8 alkane, wherein preferred acetone, ethanol, ether, methylene dichloride, the above-mentioned organic solvent of 75%-95% and the mixing solutions of water, the mixed solvent that contains the above-mentioned organic solvent of 5%-25% sherwood oil or normal hexane, more preferably acetone.Illustrate a bit be soak to extract each extraction time should be longer so that guarantee yield, be advisable in general 24-48 hour.Refluxing extraction each extraction time is typically chosen in 1-6 hour according to different solvents and gets final product through optimizing.Extraction time and number of times are only influential to yield, but do not influence the target compound that finally obtains, and do not hinder the enforcement of method of the present invention.
In the preferred embodiment of the invention, wherein said esterification step be the extracting solution that will obtain with organic solvent extraction be concentrated into do after, add methyl alcohol, reaction in the presence of acid, after reaction finishes,, separate organic phase with organic solvent and water or buck extraction, drying concentrates and obtains pheophorbide A methyl esters crude product; Wherein said acid is selected from inorganic acid, as: the vitriol oil, hydrogenchloride etc.; Or organic acid, as methylsulfonic acid, tosic acid etc., preferably sulfuric acid; The organic solvent that adopts during described the extraction is selected from C1-C2 halogenated alkane, C4-C6 ether, C3-C6 ester, preferred methylene dichloride, t-butyl methyl ether, ethyl acetate, more preferably methylene dichloride; The preferred sodium bicarbonate aqueous solution of described buck, dilute sodium hydroxide aqueous solution.
In the preferred embodiment of the invention, wherein said purification step is to concentrate the crude product organic solvent dissolution that obtains after esterification reaction of organic acid, add sherwood oil or C5-C8 alkane and produce precipitation, extremely approaching colourless with sherwood oil or the washing of C5-C8 alkane, drying obtains pheophorbide A methyl esters; The organic solvent that wherein said dissolving crude product adopts is selected from C6-C8 aromatic hydrocarbon and C1-C2 halohydrocarbon, preferred methylene dichloride, toluene and benzene, more preferably methylene dichloride; The preferred normal hexane of described C5-C8 alkane.This step purpose is to remove remaining low polar impurity, as: carotenoid compounds etc., these compounds color in solution is very dark, can pass through sherwood oil or C5-C8 alkane flush away if be adsorbed in the precipitation.
In addition, what also will illustrate a bit is, the pheophorbide A methyl esters purity very high (being preferably greater than 80%, more preferably greater than 90%) for preparing in above-mentioned steps can be used to prepare the raw material of HPPH.If will obtain more highly purified pheophorbide A methyl esters, can also further adopt in methylene chloride or methylene dichloride/ethanol system the method for recrystallization to obtain.
Based on above explanation, more in the embodiment preferred, the described method for preparing pheophorbide A methyl esters may further comprise the steps one of the present invention:
Step 1 places the acetone of 1-8 times of weight with the Taihu Lake blue-green algae, stirs to add liquid nitrogen down, until freezing curing;
Step 2 adds the acetone of 1-8 times of weight in the solid pulpous state solution that obtains, reflux or soak and extract 1 time or repeatedly, the acetone soln behind the united extraction;
Step 3 is concentrated into the acetone soln that obtains dried, adds the vitriolic methanol solution contain 2-10%, and reaction in the impouring water, use dichloromethane extraction to fully, and organic phase is concentrated, dry, obtains pheophorbide A methyl esters crude product;
Step 4 is dissolved the crude product that obtains with methylene dichloride, extremely precipitation is complete to add sherwood oil or normal hexane, filters, and the solid that obtains is extremely colourless substantially with sherwood oil or normal hexane washing, and drying obtains the pure product of pheophorbide A methyl esters.
The method of the invention, easy and simple to handle, preparation cost is cheap, and the pheophorbide A methyl esters purity height that obtains is fit to the big production demand of industry, has solved the problem of the bloom blue algae environmental pollution and the utilization of resources simultaneously.
Specific embodiments
The present invention is further described below by embodiment:
Embodiment 1.
Get Taihu Lake blue-green algae 500 grams and place 1 liter of acetone; slowly add liquid nitrogen; stirring adds 2 liters of acetone until complete freezing curing, refluxes 2 hours; filter; add 2 liters of acetone in the filter residue again, refluxed 2 hours, filter; with 500 milliliters of hot acetone washings; acetone soln after merging all and extracting is evaporated to remove fully and desolvates, under the nitrogen protection; add 500 milliliters and contain 5% vitriolic methanol solution; stirring at room 12 hours is in impouring to 1 premium on currency, with 1 liter of dichloromethane extraction; the organic phase anhydrous sodium sulfate drying is concentrated into dried.Again with 100 milliliters of methylene dichloride dissolvings, add normal hexane to precipitating fully, filter, to colourless substantially, drying obtains pheophorbide A methyl esters 2.0 and restrains the solid that obtains with the normal hexane washing.
Pheophorbide A methyl esters according to aforesaid method obtains has confirmed its structure by spectroscopy, and data are as follows:
m.p.222-224℃
UVλmax(Et
2O)667nm(5.91×10
4)，611nm(7.71×10
3)，533nm(9.73×10
3)，504nm(1.21×10
4)，407nm(1.21×10
5)；
1HNMR(400MHz，CDCl
3，δ?ppm)：9.50(s，1H，β-meso-H)，9.38(s，IH，α-meso-H)，8.56(s，1H，δ-meso-H)，8.01(m，1H，2a-H)，6.24(s，2H，10-CH
2)，6.28-6.16(m，2H，2b?&?2b’-H)，4.46(q，1H，8-H)，4.18(d，1H，7-H)，3.84(s，3H，10-CO
2CH
3)，3.64(q，2H，4a-CH
2)，3.62，3.57，3.40，3.23(4s，12H，7-CH
2CH
2CO
2 CH 3 ，5-CH
3，1-CH
3，3-CH
3)，2.64-2.25(m，4H，7-CH
2CH
2)，1.84(d，3H，8-CH
3)，1.60(t，3H，4b-CH
3)，1.45(br.s，2H，2NH)
Embodiment 2.
Get Taihu Lake blue-green algae 500 grams and place 1 liter of acetone, add dry ice, stir until complete freezing curing; add 4 liters of acetone; soaked 24 hours, and filtered, add 4 liters of acetone in the filter residue again; soaked 24 hours; filter,, merge the solution after all extractions with 500 milliliters of hot acetones washings; be evaporated to remove fully and desolvate; under the nitrogen protection, add 500 milliliters of methanol solutions (by in methyl alcohol, feeding the hydrogen chloride gas preparation) that contain 20% hydrogenchloride, reflux; stirred 1 hour; in impouring to 1 premium on currency, with 1 liter of ethyl acetate extraction, organic phase is washed with saturated sodium bicarbonate aqueous solution; anhydrous sodium sulfate drying is concentrated into dried.Again with 100 milliliters of methylene dichloride dissolvings, add sherwood oil (60-90) to precipitating fully, filter, the solid that obtains is extremely colourless substantially with sherwood oil (60-90) washing, and drying obtains pheophorbide A methyl esters 0.7 gram.
According to the pheophorbide A methyl esters that aforesaid method obtains, m.p.221-224 ℃, the numerical value of product is similar among UV spectrum and NMR (Nuclear Magnetic Resonance) spectrum numerical value and the embodiment 1.
Embodiment 3.
Get Taihu Lake blue-green algae 500 grams and place 1 liter of ether; slowly add liquid nitrogen; stirring adds 2 liters of ether until complete freezing curing, refluxes 2 hours; filter; add 2 liters of ether in the filter residue again, refluxed 2 hours, filter; with 500 milliliters of hot acetone washings; solution after merging all and extracting is evaporated to remove fully and desolvates, under the nitrogen protection; add 500 milliliters and contain 10% vitriolic methanol solution; stirring at room 12 hours is in impouring to 1 premium on currency, with 2 liters of t-butyl methyl ether extractions; the organic phase anhydrous sodium sulfate drying is concentrated into dried.Again with 100 milliliters of methylene dichloride dissolvings, add normal hexane to precipitating fully, filter, to colourless substantially, drying obtains pheophorbide A methyl esters 1.0 and restrains the solid that obtains with the normal hexane washing.
According to the pheophorbide A methyl esters that aforesaid method obtains, m.p.222-225 ℃, the numerical value of product is similar among UV spectrum and NMR (Nuclear Magnetic Resonance) spectrum numerical value and the embodiment 1.
Embodiment 4.
Get Taihu Lake blue-green algae 500 grams and place 1 liter of acetone soln; add dry ice; stirring adds 2 liter of 90% acetone (water) solution until complete freezing curing, refluxes 2 hours; filter; add 2 liter of 90% acetone (water) solution in the filter residue again, refluxed 2 hours, filter; with 500 milliliters of hot acetone washings; solution after merging all and extracting is evaporated to remove fully and desolvates, under the nitrogen protection; add 500 milliliters and contain 10% hydrogen chloride methanol solution; stirring at room 12 hours is in impouring to 1 premium on currency, with 1 liter of ethyl acetate extraction; the organic phase anhydrous sodium sulfate drying is concentrated into dried.Again with 100 milliliters of toluene dissolvings, add sherwood oil (30-60) to precipitating fully, filter, the solid that obtains is extremely colourless substantially with sherwood oil (30-60) washing, and drying obtains pheophorbide A methyl esters 1.6 grams.
According to the pheophorbide A methyl esters that aforesaid method obtains, m.p.223-225 ℃, the numerical value of product is similar among UV spectrum and NMR (Nuclear Magnetic Resonance) spectrum numerical value and the embodiment 1.
Embodiment 5.
Get Taihu Lake blue-green algae 500 grams and place 1 liter of ether; slowly add liquid nitrogen; stirring adds 2 liters of ethanolic solns that contain 15% normal hexane until complete freezing curing, soaks 24 hours; filter; add 2 liters of ethanolic solns that contain 15% normal hexane in the filter residue again, soaked 24 hours, filter; ethanolic soln washing with 500 milliliter of 15% normal hexane; solution after merging all and extracting is evaporated to remove fully and desolvates, under the nitrogen protection; add 500 milliliters and contain 3% vitriolic methanol solution; stirring at room 12 hours is in impouring to 1 premium on currency, with 1 liter of ethyl acetate extraction; the organic phase anhydrous sodium sulfate drying is concentrated into dried.Again with 200 milliliters of toluene dissolvings, extremely precipitation is complete to add normal heptane, filters, and it is extremely colourless substantially with the normal hexane washing to obtain solid, and drying obtains pheophorbide A methyl esters 1.2 grams.
According to the pheophorbide A methyl esters that aforesaid method obtains, m.p.221-223 ℃, the numerical value of product is similar among UV spectrum and NMR (Nuclear Magnetic Resonance) spectrum numerical value and the embodiment 1.
Embodiment 6.
Get Taihu Lake blue-green algae 500 grams through grinding fragmentation, place 2 liters of acetone, refluxed 2 hours; filter, add 2 liters of acetone in the filter residue again, refluxed 2 hours; filter,, merge the acetone soln after all extractions with 500 milliliters of hot acetones washings; be evaporated to remove fully and desolvate, under the nitrogen protection, add 500 ml methanol and 2.5 gram tosic acid solution; reflux 2 hours, impouring to 1 rises in the saturated sodium bicarbonate aqueous solution, with 1 liter of dichloromethane extraction; the organic phase anhydrous sodium sulfate drying is concentrated into dried.Again with 100 milliliters of methylene dichloride dissolvings, add Skellysolve A to precipitating fully, filter, to colourless substantially, drying obtains pheophorbide A methyl esters 0.9 and restrains the solid that obtains with the Skellysolve A washing.
According to the pheophorbide A methyl esters that aforesaid method obtains, m.p.221-223 ℃, the numerical value of product is similar among UV spectrum and NMR (Nuclear Magnetic Resonance) spectrum numerical value and the embodiment 1.
Claims (10)
1. method for preparing pheophorbide A methyl esters, it is characterized in that using bloom blue algae as raw material, described method comprises following four steps: (i) bloom blue algae is carried out disorganization, (ii) use organic solvent extraction, (iii) with the extractive with organic solvent esterification that obtains in the above-mentioned steps, obtain crude product, and (iv) purifying.
2. according to the process of claim 1 wherein that described bloom blue algae is the Taihu Lake blue-green algae.
3. according to the method for claim 1 or 2, wherein said disorganization step is mechanical crushing method or freezing crushing method, and wherein said Mechanical Crushing method is for example used blue-green algae cut short and ground; The freezing crushing method is to add cryogenic liquid in blue-green algae, stirs and destroys cell and tissue.
4. according to the method for claim 3, wherein said cryogenic liquid is selected from and can reaches-50 ℃ to-120 ℃ cryogenic liquid, the low-temperature solvent that low-temperature solvent that preferred liquid nitrogen, liquid nitrogen and organic solvent form or dry ice and organic solvent form, wherein said organic solvent is selected from C3-C6 ketone, the pure and mild C4-C6 ether of C1-C4 low alkyl group, preferred acetone, methyl alcohol, ethanol and ether, more preferably acetone.
5. according to each method of claim 1-4, wherein said organic solvent extraction step is to add organic solvent in the sample after historrhexis, carrying out one or many by immersion or reflux type extracts, the organic solvent that adopts when wherein extracting is selected from C3-C6 ketone, C4-C6 ether, the C1-C4 lower alkyl alcohol, the C1-C2 halogenated alkane, and the mixed solvent of above-mentioned solvent and water or C5-C8 alkane, wherein preferred acetone, ethanol, ether, methylene dichloride, the above-mentioned organic solvent of 75%-95% and the mixing solutions of water, the mixed solvent that contains the above-mentioned organic solvent of 5%-25% sherwood oil or normal hexane, more preferably acetone.
6. according to each method of claim 1-5, wherein said esterification step be the extracting solution that will obtain with organic solvent extraction be concentrated into do after, add methyl alcohol, reaction in the presence of acid, after reaction finishes,, separate organic phase with organic solvent and water or buck extraction, drying concentrates and obtains pheophorbide A methyl esters crude product.
7. according to the method for claim 6, wherein said acid is selected from inorganic acid, as: the vitriol oil, hydrogenchloride etc.; Or organic acid, as methylsulfonic acid, tosic acid etc., preferably sulfuric acid; The organic solvent that adopts during described the extraction is selected from C1-C2 halogenated alkane, C4-C6 ether, C3-C6 ester, preferred methylene dichloride, t-butyl methyl ether, ethyl acetate, more preferably methylene dichloride; The preferred sodium bicarbonate aqueous solution of described buck, dilute sodium hydroxide aqueous solution.
8. according to each method of claim 1-7, wherein said purification step is to concentrate the crude product organic solvent dissolution that obtains after esterification reaction of organic acid, add sherwood oil or C5-C8 alkane and produce precipitation, extremely approaching colourless with sherwood oil or the washing of C5-C8 alkane, drying obtains pheophorbide A methyl esters.
9. method according to Claim 8, the organic solvent that wherein said dissolving crude product adopts is selected from C6-C8 aromatic hydrocarbon and C1-C2 halohydrocarbon, preferred methylene dichloride, toluene and benzene, more preferably methylene dichloride; The preferred normal hexane of described C5-C8 alkane.
10. according to the method for claim 1, may further comprise the steps:
Step 1 places the acetone of 1-8 times of weight with the Taihu Lake blue-green algae, stirs to add liquid nitrogen down, until freezing curing;
Step 2 adds the acetone of 1-8 times of weight in the solid pulpous state solution that obtains, reflux or soak and extract 1 time or repeatedly, the acetone soln behind the united extraction;
Step 3 is concentrated into the acetone soln that obtains dried, adds the vitriolic methanol solution contain 2-10%, and reaction in the impouring water, use dichloromethane extraction to fully, and organic phase is concentrated, dry, obtains pheophorbide A methyl esters crude product;
Step 4 is dissolved the crude product that obtains with methylene dichloride, extremely precipitation is complete to add sherwood oil or normal hexane, filters, and the solid that obtains is extremely colourless substantially with sherwood oil or normal hexane washing, and drying obtains the pure product of pheophorbide A methyl esters.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462702A (en) * | 2010-11-17 | 2012-05-23 | 远东生物科技股份有限公司 | Medicinal composition capable of restraining influenza virus hemaglutinin (HA) and preparation method thereof |
| CN108030050A (en) * | 2017-12-19 | 2018-05-15 | 安徽强旺调味食品有限公司 | A kind of Islamic compound seasoner for extrusion and puffing food |
| CN110759924A (en) * | 2018-07-26 | 2020-02-07 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN112521393A (en) * | 2019-09-18 | 2021-03-19 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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2008
- 2008-03-13 CN CN200810084616A patent/CN101531663A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462702A (en) * | 2010-11-17 | 2012-05-23 | 远东生物科技股份有限公司 | Medicinal composition capable of restraining influenza virus hemaglutinin (HA) and preparation method thereof |
| CN102462702B (en) * | 2010-11-17 | 2015-02-11 | 远东生物科技股份有限公司 | Medicinal composition capable of restraining influenza virus hemaglutinin (HA) and preparation method thereof |
| CN108030050A (en) * | 2017-12-19 | 2018-05-15 | 安徽强旺调味食品有限公司 | A kind of Islamic compound seasoner for extrusion and puffing food |
| CN110759924A (en) * | 2018-07-26 | 2020-02-07 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN110759924B (en) * | 2018-07-26 | 2023-02-28 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN110759924B8 (en) * | 2018-07-26 | 2023-05-05 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN112521393A (en) * | 2019-09-18 | 2021-03-19 | 康俄(上海)医疗科技有限公司 | Preparation method of methyl pheophorbide a |
| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
| CN116162092B (en) * | 2023-03-03 | 2023-10-10 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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