CN101747338A - Method for preparing ginkgolide compound - Google Patents
Method for preparing ginkgolide compound Download PDFInfo
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- CN101747338A CN101747338A CN200810219837A CN200810219837A CN101747338A CN 101747338 A CN101747338 A CN 101747338A CN 200810219837 A CN200810219837 A CN 200810219837A CN 200810219837 A CN200810219837 A CN 200810219837A CN 101747338 A CN101747338 A CN 101747338A
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- ginkgolide
- silica gel
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Abstract
The invention relates to a method for preparing ginkgolide compound, belonging to the medicine field. The invention is characterized in that ginkgolide compound raw materials are prepared through the following method that: ginkgo leaves or ginkgo leaf extracts are taken and are extracted in aqueous solution, the obtained extract liquid is filtered and is extracted by using organic solvent, the obtained extract liquid is concentrated and is mixed with 200-mesh to 1,000-mesh silica gel, the obtained mixture is dried, eluent rich in ginkgolide compound is collected by adopting silica column chromatography, the collected eluent is crystallized to respectively obtain ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M and ginkgolide K raw materials, and the contents are respectively 90 percent to 110 percent. The invention has the advantages that the purity of the ginkgolide compound prepared through the method is high; and the preparation process is simple, the transfer rate is high, the cost is low and the industrial scale production can be realized.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of preparation method of ginkgolide compound.
Technical background
Ginkgolide compound is Ginkgo Leaf and Folium Ginkgo extract (EGB761; CP2000; CP2005) main active ingredient in; comprise bilobalide and bilobalide; wherein bilobalide mainly comprises Ginkgolide A; B; C; J; M and K monomer; bilobalide is specificity platelet activation factor (PAF) receptor blocking agent according to the literature; but all caused platelet aggregation effects of elimination PAF of dose-dependently; thereby the formation of anti-hemostasis suppository; up-to-date pharmacological research shows that ginkgolide compound has antianaphylaxis; anti-inflammatory; Antishock function also has provide protection to the rejection of ischemic injuries and organ transplantation.Bilobalide must be prepared highly purified monomeric compound to treating then special effect of nervous system disorders for improving result of treatment reduction toxic side effect.But the ginkgolide compound structure is comparatively similar, nature difference is less, make comparatively difficulty of present chemical synthesis process preparation, cost is too high, and it is also relatively more difficult to separate each monomer from Ginkgo Leaf, have only a few studies person to work out method, the patent No. is the separation purification method that discloses a kind of ginkgolide monomer in the patent of CN1680392A, and it is to adopt supercritical CO
2Refining purifying combination process, working condition is had relatively high expectations, and corresponding cost is higher.The patent No. be CN101134758A patent disclosure add the multistep composite test through twice column chromatography behind a kind of extraction using alcohol Ginkgo Leaf, and with the online detection and location of light scattering detector, by the crystallization purifying step, finally be separated to each composition of bilobalide then.Though this method conventional art has relatively had raising, whole extraction efficiency has improved 10%, and industrialization is still comparatively difficult, and cost is still higher, is difficult to industrialization.The patent No. be CN101054384A patent disclosure the purification process of a kind of lactone B, need in the technology through twice column chromatography, and wherein the Ginkgolide B composition rate of transform is less than 2%, cost is than higher.The patent No. be CN101302222A patent disclosure the Ginkgolide B composition rate of transform reach 15%, though improve a lot according to this explained hereafter cost still too high.In general obtain the ginkgolide compound extraction yield or the rate of transform at present all below 15%, production requirement is higher relatively, and production cost is also higher relatively, the suitability for industrialized production difficulty.
Summary of the invention
The object of the present invention is to provide that a kind of production cost is low, technology is simple and is convenient to the method for preparing ginkgolide compound of suitability for industrialized production.
A kind of ginkgolide compound, it is characterized in that this ginkgolide compound is to be prepared from by the following method: get Ginkgo Leaf or Folium Ginkgo extract, in the aqueous solution, extract, adopt organic solvent extraction behind the extracting liquid filtering, the extraction liquid that obtains concentrates the back and adds 200 orders-1000 order silica gel combination drying, and with 200 orders-1000 order silica gel as the column chromatography filler, adopt silica gel column chromatography to collect the elutriant that is rich in ginkgolide compound, obtain Ginkgolide A, B, C, J, M, K raw material respectively through crystallization; Content is respectively 50%-110%, and refining is 90%-110%.
Add the water yield among the above-mentioned preparation method and be Ginkgo Leaf or Folium Ginkgo extract quality 1 to 100 times, be preferably 5-20 doubly;
Water liquid pH value is 1-10 among the above-mentioned preparation method, is preferably 2-8, can add configurations such as all kinds of acid, basic cpd and salt thereof such as sodium-acetate, citric acid, sodium bicarbonate and form;
Water liquid consumption is meant and adds the water yield or extract back concentrated liquid amount among the above-mentioned preparation method;
Ginkgo Leaf or Folium Ginkgo extract extraction time 5min-360min in water is preferably 30-60min among the above-mentioned preparation method;
Organic solvent described in the above-mentioned preparation method is one or more in sherwood oil, ethyl acetate, propyl carbinol, Skellysolve A, normal hexane, the hexanaphthene, and consumption is 1-10 a times of water liquid weight, is preferably 2-5 doubly;
Used silica gel comprises silica gel G or silica gel H for silica gel commonly used among the above-mentioned preparation method.
Used silica gel is the 200-1000 order among the above-mentioned preparation method, is preferably 200 orders-400 order, 200-300 order more preferably, and silica gel consumption and Ginkgo Leaf or Folium Ginkgo extract weight ratio are 1: 0.1-1: 100, be preferably 1: 0.3-1: 10;
Used silica gel post eluting solvent is one or more in sherwood oil, ethyl acetate, propyl carbinol, Skellysolve A, normal hexane, hexanaphthene, the acetone among the above-mentioned preparation method;
The final gained Ginkgolide A of the present invention, B, C, J, M, K content can reach 90%-110%.
The prepared Ginkgolide A of the present invention, B, C, J, M, K can be used as the raw material in medicine, the healthcare products.
Adopt the thin silica gel of 200 orders-1000 purpose to have following advantage among the present invention:
The order number is relatively poor greater than 200 order silica gel separating effects, thereby loses morely, causes the composition rate of transform lower, the present invention adopts silica gel order number littler, particle is thinner, and resolution is higher, and the post height just has good resolution when being 5cm, and lose little rate of transform height, gained Ginkgolide A of the present invention, B, C, J, M, the K rate of transform all reach more than 50%, and the order number is less than 1000 order silica gel, and post is pressed too high during wash-out, production unit requires too high, and production efficiency is lower.
Embodiment
Below by part embodiment, the present invention is further described, and the preparation method is not limited to described in the embodiment:
Embodiment 1
Take by weighing Ginkgo Leaf 10kg, add water extraction 30min, filter, obtain extracting solution 300L, use the 3000L petroleum ether extraction, extraction liquid is concentrated in right amount, add an amount of 200-300 order silica gel, mixing oven dry, last silicagel column, with sherwood oil: ethyl acetate is that 1: 1 ratio preparation moving phase is carried out wash-out, collects bilobalide-containing A 50L effluent liquid, concentrates the dried dried cream of 11g that obtains, add 110ml 95% alcohol crystal, obtain the 3.45g Ginkgolide A, wherein, Ginkgolide A content is 92.9%.
Embodiment 2
Take by weighing Ginkgo Leaf 10kg, adding citric acid adjusting water liquid pH is 4.5, extract 60min, filter, obtain extracting solution 500L, use the 2000L n-butanol extraction, extraction liquid is concentrated in right amount, add an amount of 300-400 order silica gel, mixing oven dry, last silicagel column, with propyl carbinol: acetone is that 6: 4 ratio is prepared moving phase and carried out wash-out, collect bilobalide-containing B 40L effluent liquid, concentrate the dried dried cream of 9g that obtains, add the 150ml95% alcohol crystal, obtain the 2.28g Ginkgolide B, wherein, Ginkgolide B content is 102.1%.
Embodiment 3
Take by weighing Ginkgo Leaf 10kg, adding sodium-acetate adjusting water liquid pH is 8.5, extracts 40min, filter, obtain extracting solution 200L, use the 2500L n-hexane extraction, extraction liquid is concentrated in right amount, adds an amount of 200-300 order silica gel, the mixing oven dry, last silicagel column carries out wash-out with ethyl acetate, collects bilobalide-containing C 60L effluent liquid, concentrate the dried dried cream of 14g that obtains, add the 150ml95% alcohol crystal, obtain the 2.92g ginkalide C, wherein, ginkalide C content is 95.9%.
Embodiment 4
Take by weighing Folium Ginkgo extract (meeting EGB761 requires) 1kg, adding pH is 7.5 alkali aqueous solutions, filters, obtain filtrate 10L, use the 20L ethyl acetate extraction, extraction liquid is concentrated in right amount, add an amount of 300-400 order silica gel, mixing oven dry, last silicagel column, with normal hexane: sherwood oil is 7: 3 a ratio preparation moving phase, collects the 45L effluent liquid, is concentrated into the dried cream of the dried 6g of obtaining, add the 120ml95% alcohol crystal, obtain the 2.37g bilobalide J, wherein, bilobalide J content is 98.7%.
Embodiment 5
Take by weighing Folium Ginkgo extract (meeting CP2000 requires) 1kg, adding pH is 3.5 aqueous acids, filters, obtain filtrate 15L,, extraction liquid is concentrated in right amount with the extraction of 40L hexanaphthene, add an amount of 200-240 order silica gel, mixing oven dry, last silicagel column, with sherwood oil: ethyl acetate is 4: 6 a ratio preparation moving phase, collects the 40L effluent liquid, is concentrated into the dried cream of the dried 5g of obtaining, add the 150ml95% methanol crystallization, obtain 2.14g bilobalide M, wherein, bilobalide M content is 100.7%.
Embodiment 6
Take by weighing Folium Ginkgo extract (meeting CP2005 requires) 1kg, add the aqueous solution, filter, obtain filtrate 10L, use the 30L n-butanol extraction, extraction liquid is concentrated in right amount, add an amount of 240-280 order silica gel, mixing oven dry, last silicagel column, with propyl carbinol: ethyl acetate is 3: 7 a ratio preparation moving phase, collects the 40L effluent liquid, is concentrated into the dried cream of the dried 4g of obtaining, add the 100ml95% methanol crystallization, obtain the 2.04g bilobalide K, wherein, bilobalide K content is 101.8%.
Embodiment 7
Take by weighing Folium Ginkgo extract (meeting CP2000 requires) 1kg, adding citric acid adjusting water liquid pH is 3.5, extracts 40min, filter, obtain extracting solution 10L, use the 25L ethyl acetate extraction, extraction liquid is concentrated in right amount, add an amount of 200-300 order silica gel, mixing oven dry, last silicagel column, with hexanaphthene: ethyl acetate is 9: 1-1: 9 carry out gradient elution, collect bilobalide-containing A40L effluent liquid, bilobalide-containing B 40L effluent liquid, bilobalide-containing C 40L effluent liquid concentrates the dried 14g that obtains respectively, 13g, the dried cream of 14g adds the 150ml95% alcohol crystal respectively, obtains the 2.92g Ginkgolide A, 2.58g Ginkgolide B, 1.58g ginkalide C, wherein, Ginkgolide A content is 95.9%, Ginkgolide B content 98.2%, ginkalide C content are 93.1%.
Claims (10)
1. ginkgolide compound raw materials, it is characterized in that this ginkgolide compound is to prepare by the following method: get Ginkgo Leaf or Folium Ginkgo extract, in the aqueous solution, extract, adopt organic solvent extraction behind the extracting liquid filtering, the extraction liquid that obtains concentrates the back and adds 200-1000 order silica gel combination drying, and with 200-1000 order silica gel as the column chromatography filler, adopt silica gel column chromatography to collect the elutriant that is rich in ginkgolide compound, obtain Ginkgolide A, B, C, J, M, K raw material respectively through crystallization, content is respectively 90%-110%.
2. according to ginkgolide compound described in the claim 1, it is characterized in that aqueous ph value is 1-10, be preferably 2-8, can add configurations such as all kinds of acid, basic cpd and salt thereof such as sodium-acetate, citric acid, sodium bicarbonate and form.
3. according to ginkgolide compound described in the claim 1, it is characterized in that amount of aqueous solution used is Ginkgo Leaf or Folium Ginkgo extract quality 1 to 100 times, be preferably 5-20 doubly.
4. according to ginkgolide compound described in the claim 1, it is characterized in that described amount of aqueous solution used is meant the water yield or the extraction back concentrated liquid amount of adding.
5. according to ginkgolide compound described in the claim 1, it is characterized in that Ginkgo Leaf or Folium Ginkgo extract extraction time 5min-360min in water, be preferably 30-60min.
6. according to ginkgolide compound described in the claim 1, the organic solvent that it is characterized in that the extraction of water liquid is one or more in sherwood oil, ethyl acetate, propyl carbinol, Skellysolve A, normal hexane, the hexanaphthene, consumption is 1-10 a times of water liquid weight, is preferably 2-5 doubly.
7. according to ginkgolide compound described in the claim 1, it is characterized in that used silica gel is a silica gel commonly used, comprises silica gel G or silica gel H.
8. according to silica gel described in the claim 7, the order number is 200 order to 1000 orders, is preferably 200 order to 400 orders, more preferably 200 order to 300 orders, silica gel consumption and Ginkgo Leaf or Folium Ginkgo extract weight ratio are 1: 0.1-1: 100, be preferably 1: 0.3-1: 10.
9. according to ginkgolide compound described in the claim 1, it is characterized in that used silica gel post eluting solvent is one or more in sherwood oil, ethyl acetate, propyl carbinol, Skellysolve A, normal hexane, hexanaphthene, the acetone.
10. according to ginkgolide compound described in the claim 1, it is characterized in that gained Ginkgolide A, B, C, J, M, K content are respectively 90%-110%, prepared Ginkgolide A, B, C, J, M, K can be used as the raw material in medicine, the healthcare products.
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| CN200810219837A CN101747338A (en) | 2008-12-11 | 2008-12-11 | Method for preparing ginkgolide compound |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159619A (en) * | 2011-12-15 | 2013-06-19 | 张加明 | Industrialization production technology for extracting ginkgolic acid and bilobalide from Ginkgo testa |
| CN104447790A (en) * | 2013-09-22 | 2015-03-25 | 江苏康缘药业股份有限公司 | Separation and purification method for ginkgolide B |
| CN105061458A (en) * | 2015-09-01 | 2015-11-18 | 合肥工业大学 | Preparation method of nontoxic high-purity ginkgo total lactones and monomers thereof |
| CN105524077A (en) * | 2015-11-18 | 2016-04-27 | 江苏康缘药业股份有限公司 | K crystal form of ginkgolide K, and preparation method, composition and application thereof |
| CN105585576A (en) * | 2015-11-18 | 2016-05-18 | 江苏康缘药业股份有限公司 | Bilobalide K crystal L type and preparation method, composition and application thereof |
| CN107129505A (en) * | 2017-06-01 | 2017-09-05 | 陕西理工大学 | The industrial production process of lactone constituents high-purity monomer in a kind of ginkgo leaf purification |
| CN108892673A (en) * | 2018-09-01 | 2018-11-27 | 陈燕飞 | A kind of extracting method of ginkgolide compound |
| WO2019140793A1 (en) * | 2018-01-19 | 2019-07-25 | 上海上药杏灵科技药业股份有限公司 | Preparation method for high-purity total lactones of ginkgo bilobal. and application thereof |
| CN111171043A (en) * | 2020-02-26 | 2020-05-19 | 克拉玛依市人民医院 | Method for extracting ginkgolide B |
-
2008
- 2008-12-11 CN CN200810219837A patent/CN101747338A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159619A (en) * | 2011-12-15 | 2013-06-19 | 张加明 | Industrialization production technology for extracting ginkgolic acid and bilobalide from Ginkgo testa |
| CN104447790A (en) * | 2013-09-22 | 2015-03-25 | 江苏康缘药业股份有限公司 | Separation and purification method for ginkgolide B |
| CN105061458A (en) * | 2015-09-01 | 2015-11-18 | 合肥工业大学 | Preparation method of nontoxic high-purity ginkgo total lactones and monomers thereof |
| CN105524077A (en) * | 2015-11-18 | 2016-04-27 | 江苏康缘药业股份有限公司 | K crystal form of ginkgolide K, and preparation method, composition and application thereof |
| CN105585576A (en) * | 2015-11-18 | 2016-05-18 | 江苏康缘药业股份有限公司 | Bilobalide K crystal L type and preparation method, composition and application thereof |
| CN105585576B (en) * | 2015-11-18 | 2019-01-15 | 江苏康缘药业股份有限公司 | Bilobalide K crystalline substance L-type and preparation method and its composition and purposes |
| CN105524077B (en) * | 2015-11-18 | 2019-03-01 | 江苏康缘药业股份有限公司 | Bilobalide K crystalline substance K-type and preparation method and its composition and purposes |
| CN107129505A (en) * | 2017-06-01 | 2017-09-05 | 陕西理工大学 | The industrial production process of lactone constituents high-purity monomer in a kind of ginkgo leaf purification |
| CN107129505B (en) * | 2017-06-01 | 2019-03-29 | 陕西理工大学 | The industrial production process of lactone element monomers in a kind of ginkgo leaf purification |
| WO2019140793A1 (en) * | 2018-01-19 | 2019-07-25 | 上海上药杏灵科技药业股份有限公司 | Preparation method for high-purity total lactones of ginkgo bilobal. and application thereof |
| CN108892673A (en) * | 2018-09-01 | 2018-11-27 | 陈燕飞 | A kind of extracting method of ginkgolide compound |
| CN111171043A (en) * | 2020-02-26 | 2020-05-19 | 克拉玛依市人民医院 | Method for extracting ginkgolide B |
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Application publication date: 20100623 |