CN103145653A - High-efficiency extraction and purification process for 10-deacetyl baccatin (10-DAB) III - Google Patents
High-efficiency extraction and purification process for 10-deacetyl baccatin (10-DAB) III Download PDFInfo
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- CN103145653A CN103145653A CN2013101252999A CN201310125299A CN103145653A CN 103145653 A CN103145653 A CN 103145653A CN 2013101252999 A CN2013101252999 A CN 2013101252999A CN 201310125299 A CN201310125299 A CN 201310125299A CN 103145653 A CN103145653 A CN 103145653A
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Abstract
The invention discloses a process for preparing 10-deacetyl baccatin (10-DAB) by taking branches and leaves of Taxus chinensis as raw materials. The 10-DAB is an important raw material which is used for synthetizing anticancer drugs which are exact in curative effect and unique in pharmacologic action, such as taxol and docetaxel. According to the process for preparing the 10-DAB by taking the branches and leaves of the Taxus chinensis as the raw materials, the 10-DAB is obtained by the following steps of: soaking and extracting the branches and leaves of the Taxus chinensis by an organic solvent, dissolving and decontaminating and extracting the branches and leaves of the Taxus chinensis by the organic solvent and purifying in a special solvent. The content of the 10-DAB obtained by the process is at least 96.5 percent, and the yield reaches 67.2 percent.
Description
Technical field
The present invention relates to a kind of preparation of chemical intermediate, a kind of simple efficiently extracting and purifying obtains the processing method of 10-deacetylate baccatin III (hereinafter to be referred as 10-DAB) take Ramulus et folium taxi cuspidatae as raw material.
Background technology
Cancer has become one of main illness of serious threat human health, and annual approximately have 6,000,000 new cases to be in the news, and due to the difficulty of early diagnosis of cancer, a considerable amount of cancer patientss will rely on pharmacological agent.Taxol has very unique anticancer mechanism, and ovarian cancer, nonsmall-cell lung cancer, mammary cancer, leukemia, melanoma and colorectal carcinoma etc. are all had good curative effect.Mainly to make the mitotic division of tumour cell stop causing death of neoplastic cells by suppressing microtubule depolymerization, also having by impact and participate in apoptotic enzyme and activate the ability that promotes apoptosis of tumor cells with apoptosis-related protein, is uniquely can impel microtubule to form and suppress the Secondary Metabolism of Plant product of tubulin depolymerization at present.Taxol has become the representative of new generation anti-cancer medicament because of its unique mechanism of action.Up to now, taxol more than 40 country's listings in the whole world.Unique to kinds cancer determined curative effect, pharmacological action because of it, taxol is since listing in 1992, and sales volume increases rapidly with the net value of average annual 500000000 dollars.
Taxol mainly contains following source at present, and the one, by directly extracting from perennial bark of Ramulus et folium taxi cuspidatae.taked the adverse current partition chromatography of 400 test tubes in 1966, extract the 0.5g taxol from the bark of Ramulus et folium taxi cuspidatae of 12kg Pacific Ocean, last 2 years, its technique is very loaded down with trivial details, and exist production technology level to fall behind, reliability of technology, repeated and stable extreme difference, yield is extremely low, fluctuation range is large, produce the waste of Raw and auxiliary material large, the defectives such as production cost height, because of taxol in bark content in 0.06% left and right, and bark is non-renewable resources, with this kind method, yield is extremely low, can only satisfy the short-term needs, and sacrifice in a large number limited taxus resource, therefore for solving resource problem, the scientists in the whole world is improved extraction and purification process except optimizing, improve outside productive rate, complete synthesis, the direction such as semi-synthetic has also been done large quantity research.The 2nd, complete synthesizing process, 1994, Nincolaou etc. used the strategic complete synthesis taxol of retrosynthetic analysis method, but the reaction needed 22-25 step, the process complexity, total recovery is too low, and cost is higher, is difficult to form industrialization production.The 3rd, cell culture method, but its maximum output is only 22mg/L, and cost is high, and also faces a series of difficult problems, and its market competitiveness is low, is difficult to realize industrialization.The 4th, extract the semi-synthetic taxol of precursor from the branches and leaves of Chinese yew genus plants, 1988, reported first such as France Denis etc. is semi-synthetic taxol take 10-DAB as raw material, 10-DAB mainly is distributed in the branches and leaves of annual Ramulus et folium taxi cuspidatae, its content is more than 0.1%, because branches and leaves are renewable resources, and 10-DAB in Ramulus et folium taxi cuspidatae content than abundant many of taxol, the yield of separation and Extraction makes semisynthesis more and more come into one's own also higher than taxol.
10-DAB, the white powder crystallization, molecular formula is C
29H
36O
10, from the extraction of the branches and leaves of Chinese yew genus plants, for the synthesis of the anticarcinogen taxol.Existing extraction process has acetone/ethyl acetate mixture refluxing extraction to pulverize Ramulus et folium taxi cuspidatae, reclaims solvent and gets medicinal extract, aqueous suspension medicinal extract dichloromethane extraction, column chromatographic isolation and purification.Organic acid soaks the Ramulus et folium taxi cuspidatae of pulverizing, and the leaching liquid organic solvent extraction that obtains boils off solvent, obtains adding the acetonitrile dissolving in glutinous shape thing, and the gained mixture is placed cooling crystallization, obtains crude product (patent publication No. CN1903849).Xiao Hu applies for a patent the Ramulus et folium taxi cuspidatae that (publication number CN101230053A) adopts the citric acid supersound extraction to pulverize, the extracting solution absorption with macroporous adsorbent resin that obtains, use again ethanol elution, the evaporate to dryness dissolving obtains tawny extract condensed cream, and organic solvent dissolution is removed insolubles, solvent evaporated, recrystallization obtains target product 10-DAB, and purity reaches 98%, but productive rate is very low.
Summary is got up, and above 10-DAB extracts the preparation method and has following defective:
(1) reaction not exclusively, can't extract 10-DAB from Ramulus et folium taxi cuspidatae fully;
(2) the solvent usage quantity is large, and impurity is many, and difficult quality is controlled, and productive rate is low, causes production cost high;
(3) processing sequence is numerous and diverse, and energy consumption is large, is not suitable for suitability for industrialized production;
The present invention further studies for overcoming above-mentioned weak point, and its technique is improved, and invents the low-cost suitable large industrial 10-DAB extraction and purification process of a high yield and high quality.
Summary of the invention
Purpose of the present invention: the extraction and purification process of inventing a kind of 10-DAB high yield and high quality of, energy-saving low-carbon environmental protection simple to operation as the raw material reaction flow process take Ramulus et folium taxi cuspidatae.
(1) with after the Ramulus et folium taxi cuspidatae bake drying, to pulverize 60 orders-80 mesh sieve and got powder, 5 times of volume cold soakings of acetone/ethyl acetate (1: 1) extract 24h, repeat 3 times, reclaim solvent and get medicinal extract, the solvent recuperation reusable edible;
(2) medicinal extract that the upper step was obtained is with 3 times of amount dissolve with ethanol solution, and 0 ℃ is standing, the centrifugal chlorophyll of removing, and concentrating under reduced pressure reclaims solvent and gets paste, removes the waste that chlorophyll can greatly reduce the next step solvent, is more conducive to the purification step of follow-up crude product;
(3) remove chlorophyllous pure cream with dichloromethane extraction, extract and remove by filter insolubles 3 times, then add the mixing solutions extraction of 20% ethanol and 2% sodium hydroxide, the extraction liquid anhydrous sodium sulfate drying reclaims the solvent reusable edible.Directly use suspension medicinal extract dichloromethane extraction than traditional technology, reduce emulsification, save the solvent usage quantity, improve yield and the content of 10-DAB;
(4) do not adopt column chromatographic isolation and purification, directly obtain target product with methanol-water crystallization and sherwood oil-acetone recrystallization, content is more than 96.5%, and yield reaches 67.2%.
Raw material drying of the present invention is pulverized the organic solvent cold soaking again and is extracted, and reduce the reaction solvent usage quantity and improve simultaneously yield, the recyclable recycling of solvent, environmental protection, this technological operation is simple, efficient, the energy-saving low-carbon environmental protection, is fit to industrialized production.
Description of drawings
Fig. 1 is the structural formula of 10-DAB
Fig. 2 is 10-DAB extraction process schema
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Embodiment 1
Take Ramulus et folium taxi cuspidatae 10kg, drying and crushing is crossed 80 mesh sieves, adds ethyl acetate/acetone (1: 1) 50.0L cold soaking to extract 24h, repeats 3 times, the recovery solvent cycle is utilized, get medicinal extract, 30L alcohol heating reflux dissolving medicinal extract adds 9L water, 0 ℃ standing, centrifugal, vacuum-concentrcted reclaims solvent and gets paste, the ethanol recycle and reuse; Add the pure cream of methylene dichloride dissolving, extract and remove insolubles 3 times, add the extraction of 20% ethanol and 2% sodium hydroxide mixing solutions, extraction liquid gets medicinal extract with anhydrous sodium sulfate drying; With methanol-water crystallization and sherwood oil-acetone recrystallization, obtain the 10-DAB elaboration, HPLC detection level 96.6%, yield 67.2%.
Embodiment 2
Take Ramulus et folium taxi cuspidatae 10kg, drying and crushing is crossed 50 mesh sieves, adds ethyl acetate/acetone (1: 1) 50.0L cold soaking to extract 24h, repeats 3 times, the recovery solvent cycle is utilized, get medicinal extract, 30L alcohol heating reflux dissolving medicinal extract adds 9L water, 0 ℃ standing, centrifugal, vacuum-concentrcted reclaims solvent and gets paste, the ethanol recycle and reuse; Add the pure cream of methylene dichloride dissolving, extract and remove insolubles 3 times, add the extraction of 20% ethanol and 2% sodium hydroxide mixing solutions, extraction liquid gets medicinal extract with anhydrous sodium sulfate drying; Add methanol-water crystallization and sherwood oil-acetone recrystallization, obtain the 10-DAB elaboration, HPLC detection level 95.3%, yield 63.5%.
Embodiment 3
Take Ramulus et folium taxi cuspidatae 10kg, drying and crushing is crossed 100 mesh sieves, adds ethyl acetate/acetone (1: 1) 50.0L cold soaking to extract 24h, repeats 3 times, the recovery solvent cycle is utilized, get medicinal extract, 30L alcohol heating reflux dissolving medicinal extract adds 9L water, 0 ℃ standing, centrifugal, vacuum-concentrcted reclaims solvent and gets paste, the ethanol recycle and reuse; Add the pure cream of methylene dichloride dissolving, extract and remove insolubles 3 times, add the extraction of 20% ethanol and 2% sodium hydroxide mixing solutions, extraction liquid gets medicinal extract with anhydrous sodium sulfate drying; Add methanol-water crystallization and sherwood oil-acetone recrystallization, obtain the 10-DAB elaboration, HPLC detection level 95.1%, yield 67.3%.
Embodiment 4
Take Ramulus et folium taxi cuspidatae 10kg, drying and crushing is crossed 80 mesh sieves, adds ethyl acetate/acetone (1: 1) 50.0L cold soaking to extract 24h, repeats 3 times, the recovery solvent cycle is utilized, get medicinal extract, 30L alcohol heating reflux dissolving medicinal extract adds 9L water, 0 ℃ standing, centrifugal, vacuum-concentrcted reclaims solvent and gets paste, the ethanol recycle and reuse; Aqueous suspension medicinal extract adds dichloromethane extraction, and extraction liquid gets medicinal extract with anhydrous sodium sulfate drying; Add methanol-water crystallization and sherwood oil-acetone recrystallization, obtain the 10-DAB elaboration, HPLC detection level 61.4%, yield 62.6%.
Claims (7)
1. one kind is extracted the technique for preparing 10-DAB take Ramulus et folium taxi cuspidatae as raw material, it is characterized in that take Ramulus et folium taxi cuspidatae as raw material, the efficient extraction separation and purification technology of application of advanced, Ramulus et folium taxi cuspidatae is dry, pulverize and sieve, organic solvent soaks and extracts, and with the medicinal extract organic solvent dissolution, purification process obtains 10-DAB.
2. method according to claim 1, is characterized in that the Ramulus et folium taxi cuspidatae drying was pulverized the 60-80 mesh sieve, and the organic solvent cold soaking extracts 24h, repeats 3 times, reclaims solvent and gets medicinal extract.
3. method according to claim 2, institute is with an organic solvent acetone/ethyl acetate (V: V) 1: 1 mixed solution.
4. method according to claim 1, is characterized in that organic solvent dissolution medicinal extract, and 0 ℃ standing, and the centrifugal chlorophyll of removing gets pure cream.
5. method according to claim 4, institute is with an organic solvent ethanol.
6. method according to claim 1, adopt dichloromethane extraction to remove chlorophyllous pure cream, removes by filter insolubles, then add the mixing solutions extraction of 20% ethanol and 2% sodium hydroxide.
7. method according to claim 1, is characterized in that obtaining 10-DAB with methanol-water crystallization and sherwood oil-acetone recrystallization extraction liquid, and content is more than 96.5%, and yield reaches 67.2%.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104031008A (en) * | 2014-06-30 | 2014-09-10 | 牛兆颖 | Method for preparing taxol crude extract |
| CN110003145A (en) * | 2019-04-15 | 2019-07-12 | 云南汉德生物技术有限公司 | A method of extracting 10- deacetylate Bakating III from Chinese yew |
| CN110551081A (en) * | 2019-09-26 | 2019-12-10 | 江苏红豆杉药业有限公司 | method for extracting 10-deacetylation baccatin III from taxus mairei |
| CN113244522A (en) * | 2021-04-29 | 2021-08-13 | 蔡业光 | Anhydrous purification process, transdermal drug delivery device and use method of anhydrous purification process |
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| US5763477A (en) * | 1994-07-22 | 1998-06-09 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III |
| CN1442413A (en) * | 2003-04-18 | 2003-09-17 | 北京怡禾生物工程有限公司 | Method of extracting medical taxadol and its derivative using regenerable resources |
| CN102212045A (en) * | 2010-04-08 | 2011-10-12 | 常山曼地亚红豆杉科技开发有限公司 | Method for simultaneously extracting taxol and 10-DABIII (10-deacetyl baccatine III) from branches and leaves of Taxus media |
-
2013
- 2013-04-12 CN CN2013101252999A patent/CN103145653A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5763477A (en) * | 1994-07-22 | 1998-06-09 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III |
| CN1442413A (en) * | 2003-04-18 | 2003-09-17 | 北京怡禾生物工程有限公司 | Method of extracting medical taxadol and its derivative using regenerable resources |
| CN102212045A (en) * | 2010-04-08 | 2011-10-12 | 常山曼地亚红豆杉科技开发有限公司 | Method for simultaneously extracting taxol and 10-DABIII (10-deacetyl baccatine III) from branches and leaves of Taxus media |
Non-Patent Citations (1)
| Title |
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| 王小刚等: "东北红豆杉枝叶中紫杉醇和10-脱乙酰巴卡亭的分离纯化及检测", 《食品与药品》, vol. 8, no. 12, 31 December 2006 (2006-12-31), pages 36 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104031008A (en) * | 2014-06-30 | 2014-09-10 | 牛兆颖 | Method for preparing taxol crude extract |
| CN104031008B (en) * | 2014-06-30 | 2015-12-09 | 牛兆颖 | A kind of preparation method of taxol crude extract |
| CN110003145A (en) * | 2019-04-15 | 2019-07-12 | 云南汉德生物技术有限公司 | A method of extracting 10- deacetylate Bakating III from Chinese yew |
| CN110551081A (en) * | 2019-09-26 | 2019-12-10 | 江苏红豆杉药业有限公司 | method for extracting 10-deacetylation baccatin III from taxus mairei |
| CN110551081B (en) * | 2019-09-26 | 2021-06-11 | 无锡紫杉药业有限公司 | Method for extracting 10-deacetylation baccatin III from taxus mairei |
| CN113244522A (en) * | 2021-04-29 | 2021-08-13 | 蔡业光 | Anhydrous purification process, transdermal drug delivery device and use method of anhydrous purification process |
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Application publication date: 20130612 |