CN102911183A - Method for preparing artemether from artemether synthetic mother liquor - Google Patents
Method for preparing artemether from artemether synthetic mother liquor Download PDFInfo
- Publication number
- CN102911183A CN102911183A CN2011102210782A CN201110221078A CN102911183A CN 102911183 A CN102911183 A CN 102911183A CN 2011102210782 A CN2011102210782 A CN 2011102210782A CN 201110221078 A CN201110221078 A CN 201110221078A CN 102911183 A CN102911183 A CN 102911183A
- Authority
- CN
- China
- Prior art keywords
- artemether
- elutriant
- mother liquid
- synthesis mother
- acetone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a method for preparing artemether from artemether synthetic mother liquor. The method includes: using organic solvent to dissolve solid obtained by concentrating and drying artemether synthetic mother liquor, sampling on a macroporous resin column, using acetone with the volume concentration of 20-70% for eluting, performing thin layer chromatographic detection, and fractionally collecting eluant containing alpha-artemether and eluant containing beta-artemether; and respectively recovering solvents in the eluant containing alpha-artemether and the eluant containing beta-artemether, filtering to obtain crude alpha-artemether and crude beta-artemether, using ethanol to dissolve the crude alpha-artemether and the crude beta-artemether, and adding water for crystallization to obtain alpha-artemether and beta-artemether. Compared with the prior art, the method has the advantages that the alpha-artemether and the beta-artemether are successively separated from the artemether synthetic mother liquor, filler for chromatography is cheap and simple in regeneration, and elution solvent is simple and easy to recovery; and the whole process is simple and easy to control, the production cost is low, and industrial production is easier to implement.
Description
Technical field
The present invention relates to the preparation method of Artemether, be specifically related to from the Artemether synthesis mother liquid, prepare the method for Artemether.
Background technology
Artemether (methyldihydroartemisinine, MDA) be the methyl-etherified derivative of Dihydroartemisinin, by extracting Artemisinin in the plant chrysanthemum sweet wormwood, the derivative of the sesquiterpene lactones Artemisinin that obtains after semi-synthetic, its epimer β-Artemether is the first-selected antimalarial drug of world health organisation recommendations, is the kind new medicine that China develops voluntarily and admitted in the world.Artemether the treatment plasmodium falciparum (Plasmodium falciparum) many resistances and concurrent strain (complicated strains) than Artemisinin better effects if.But the αisomer of Artemether meeting generation about 20% in preparation process is α-Artemether, and α-Artemether does not have Antimalarial, just uses as standard substance in detecting β-Artemether.
At present, the industrial synthetic method that all adopts prepares Artemether, also contain a certain amount of Artemether in the Artemether synthesis mother liquid that produces in the preparation process, wherein α-Artemether and β-Artemether respectively accounts for 50% approximately, because the method with common recrystallization or extraction can't make qualified β Artemether from synthesis mother liquid, therefore Artemether manufacturing enterprise just directly discharges after synthesis mother liquid is reclaimed solvent, and this has caused larger waste.If can from synthesis mother liquid, isolate qualified β-Artemether, will improve the productive rate of β-Artemether, and bring larger economic benefit.Existing few about the research of Artemether synthesis mother liquid, the people such as Xie Xiaotian (herbal medicine the 5th phase of the 32nd volume calendar year 2001,388～389) separation of a new constituent and identify and disclose the scheme of from synthesis mother liquid, isolating α-Artemether in the literary composition in the Artemether synthesis mother liquid, specifically with Artemether synthesis mother liquid dichloromethane extraction, concentrated, then use petroleum ether dissolution, concentrated by 3 silica gel column chromatographies separation, more respectively with sherwood oil-vinyl acetic monomer; Sherwood oil-ether wash-out, crystallization obtains α-Artemether.Though aforesaid method can be isolated α-Artemether, it adopts silicagel column to separate, and adopts complicated eluent, has the deficiencies such as production cost height and silica regeneration complexity, is difficult to apply industrial.
Summary of the invention
The technical problem to be solved in the present invention provides the method for preparing Artemether from the Artemether synthesis mother liquid that a kind of production cost is low, technique is simple and easy to control.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
The method that from the Artemether synthesis mother liquid, prepares Artemether, get the Artemether synthesis mother liquid through solid concentrated, dry gained, with upper macroporous resin column behind the organic solvent dissolution, it is 20～70% acetone wash-out with volumetric concentration, thin-layer chromatography detects, and Fractional Collections contains the elutriant of α-Artemether and contains the elutriant of β-Artemether; Reclaim respectively the elutriant of the above-mentioned α of containing-Artemether and contain solvent, filtration in the elutriant of β-Artemether, obtain α-Artemether crude product and β-Artemether crude product, carry out crystallization with adding water behind the dissolve with ethanol respectively again, namely get α-Artemether and β-Artemether.
In the technique scheme:
The model of described macroporous resin column is D101, D102 or AB-8.
Described organic solvent can be methylene dichloride, methyl alcohol, acetone, ethyl acetate, acetonitrile or ethanol, preferably uses acetone, is beneficial to the recovery of follow-up solvent; Its consumption gets final product through solid concentrated, dry gained for all dissolving by the Artemether synthesis mother liquid.
When wash-out, the volumetric concentration of acetone can obtain better separating effect 40～60% the time.
In whole elution process, the flow rate control of liquid at 5～6ml/min for well.
Technique scheme can be isolated α-Artemether and β-Artemether preferably, but the time of wash-out can be longer when separating, in order to shorten the time of wash-out, improved technical scheme on the basis of the above below can adopting: get the Artemether synthesis mother liquid through concentrated, the solid of dry gained, with upper macroporous resin column behind the organic solvent dissolution, it is first 20～70% acetone wash-out with volumetric concentration, thin-layer chromatography detects, collection contains the elutriant of α-Artemether, be 70～100% acetone wash-outs with volumetric concentration again, thin-layer chromatography detects, and collects the elutriant that contains β-Artemether; Reclaim respectively the elutriant of the above-mentioned α of containing-Artemether and contain solvent, filtration in the elutriant of β-Artemether, obtain α-Artemether crude product and β-Artemether crude product, carry out crystallization with adding water behind the dissolve with ethanol respectively again, namely get α-Artemether and β-Artemether.The elutriant concentration of this technical scheme when follow-up wash-out β-Artemether is higher, can be better with β-Artemether wash-out out, in addition since before α-Artemether is all washed out, thereby can be without coutroi velocity, thus accelerate the speed of whole elution process.
In the above-mentioned improved technical scheme:
The model of described macroporous resin column is D101, D102 or AB-8.
Described organic solvent dichloromethane, methyl alcohol, acetone, ethyl acetate, acetonitrile or ethanol preferably use acetone, are beneficial to the recovery of follow-up solvent; Its consumption gets final product through solid concentrated, dry gained for all dissolving by the Artemether synthesis mother liquid.
The volumetric concentration of the acetone that described wash-out α-Artemether is used is preferably 40～80%.
When collection contained the elutriant of α-Artemether, flow rate of liquid was controlled at 5～6ml/min for well.
The method of the invention adopts macroporous resin column that the Artemether synthesis mother liquid is separated, and carries out wash-out take acetone as solvent, the gained elutriant is carried out the processing such as solvent recuperation, crystallization to obtain α-Artemether and β-Artemether.Compared with prior art, the method for the invention is successively isolated α-Artemether and β-Artemether from the Artemether synthesis mother liquid, and the filler low price, the regeneration that are used for chromatography in the method are simple, and eluting solvent is simple, easily reclaims; Whole technological operation is simple and easy to control, separates the α-Artemether obtain and β-Artemether productive rate is high, purity is high by the method, and production cost is low, is easier to realize suitability for industrialized production.
Embodiment
The below further specifies the present invention with embodiment, but the present invention is not limited to these embodiment.
Below the raw material described in each embodiment all refer to the Artemether synthesis mother liquid through solid concentrated, dry gained, concrete preparation method gets the Artemether synthesis mother liquid, behind decompression recycling ethanol under 50 ℃ of conditions, cooling, filter, the gained filter cake carries out drying under 45 ℃ of conditions, and get final product.
Embodiment 1
1) takes by weighing raw material 5 grams, with upper D101 type macroporous resin column behind the 15ml acetone solution, acetone wash-out with 40% (flow velocity is 6ml/min), thin-layer chromatography detects, Fractional Collections contains the elutriant of α-Artemether and contains the elutriant of β-Artemether, reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of α-Artemether, filters, and obtains α-Artemether crude product 1.5 grams; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of β-Artemether, filters, and obtains β Artemether crude product 2.5 grams;
2) α-Artemether crude product and β-Artemether crude product are dissolved in respectively under 40 ℃ of conditions are equivalent to it separately in the ethanol of 3.3 times of weight, be dissolved rear the dropping respectively and be equivalent to its separately water of 3 times of weight, being cooled to 12 ℃ stirred 30 minutes, there are a large amount of white crystals to separate out, suction filtration, drying, get respectively α-Artemether 1.2 grams, productive rate 24%, β-Artemether elaboration 2.0 grams, productive rate 40%.
Detect through HPLC, the purity of above-mentioned gained α-Artemether and β-Artemether is respectively 99.2%, 99.1%.
Embodiment 2
1) takes by weighing raw material 5 grams, with upper D102 type macroporous resin column behind the 15ml acetone solution, acetone wash-out with 60% (flow velocity is 5ml/min), thin-layer chromatography detects, Fractional Collections contains the elutriant of α-Artemether and contains the elutriant of β-Artemether, reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of α-Artemether, filters, and obtains α-Artemether crude product 1.8 grams; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of β-Artemether, filters, and obtains β Artemether crude product 2.2 grams;
2) α-Artemether crude product and β-Artemether crude product are dissolved in respectively under 40 ℃ of conditions are equivalent to it separately in the ethanol of 4 times of weight, be dissolved rear the dropping respectively and be equivalent to its separately water of 3 times of weight, being cooled to 10 ℃ stirred 20 minutes, there are a large amount of white crystals to separate out, suction filtration, drying, get respectively α-Artemether 1.5 grams, productive rate 30%, β-Artemether elaboration 1.8 grams, productive rate 36%.
Detect through HPLC, the purity of above-mentioned gained α-Artemether and β-Artemether is respectively 99.4%, 99.0%.
Embodiment 3
1) takes by weighing raw material 10 grams, with upper AB-8 type macroporous resin column behind the 30ml dissolve with methanol, acetone wash-out with 50% (flow velocity is 6ml/min), thin-layer chromatography detects, Fractional Collections contains the elutriant of α-Artemether and contains the elutriant of β-Artemether, reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of α-Artemether, filters, and obtains α-Artemether crude product 4 grams; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of β-Artemether, filters, and obtains β Artemether crude product 5 grams;
2) α-Artemether crude product and β-Artemether crude product are dissolved in respectively under 40 ℃ of conditions are equivalent to it separately in the ethanol of 5 times of weight, be dissolved rear the dropping respectively and be equivalent to its separately water of 4 times of weight, being cooled to 12 ℃ stirred 130 minutes, there are a large amount of white crystals to separate out, suction filtration, drying, get respectively α-Artemether 3.7 grams, productive rate 37%, β-Artemether elaboration 4.2 grams, productive rate 42%.
Detect through HPLC, the purity of above-mentioned gained α-Artemether and β-Artemether is respectively 99.1%, 99.2%.
Embodiment 4
1) takes by weighing raw material 5 grams, with upper D101 type macroporous resin column behind the 15ml dissolve with ethanol, acetone wash-out with 30% (flow velocity is 5ml/min), thin-layer chromatography detects, collection contains the elutriant of α-Artemether, be 80% acetone wash-out again with volumetric concentration, thin-layer chromatography detects, and collects the elutriant that contains β-Artemether; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of α-Artemether, filters, and obtains α-Artemether crude product 1.9 grams; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of β-Artemether, obtains β Artemether crude product 2.0 grams;
2) α-Artemether crude product and β-Artemether crude product are dissolved in respectively under 35 ℃ of conditions are equivalent to it separately in the ethanol of 4 times of weight, be dissolved rear the dropping respectively and be equivalent to its separately water of 4 times of weight, being cooled to 10 ℃ stirred 20 minutes, there are a large amount of white crystals to separate out, suction filtration, drying, get respectively α-Artemether 1.5 grams, productive rate 30%, β-Artemether elaboration 1.8 grams, productive rate 36%.
Detect through HPLC, the purity of above-mentioned gained α-Artemether and β-Artemether is respectively 99.3%, 99.1%.
Embodiment 5
1) takes by weighing raw material 10 grams, with upper D101 type macroporous resin column after the dissolving of 30ml methylene dichloride, acetone wash-out with 50% (flow velocity is 6ml/min), thin-layer chromatography detects, collection contains the elutriant of α-Artemether, be 100% acetone wash-out again with volumetric concentration, thin-layer chromatography detects, and collects the elutriant that contains β-Artemether; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of α-Artemether, filters, and obtains α-Artemether crude product 3.8 grams; Reclaim under reduced pressure is above-mentioned to contain acetone in the elutriant of β-Artemether, obtains β Artemether crude product 4.5 grams;
2) α-Artemether crude product and β-Artemether crude product are dissolved in respectively under 35 ℃ of conditions are equivalent to it separately in the ethanol of 3 times of weight, be dissolved rear the dropping respectively and be equivalent to its separately water of 3 times of weight, being cooled to 10 ℃ stirred 30 minutes, there are a large amount of white crystals to separate out, suction filtration, drying, get respectively α-Artemether 3.5 grams, productive rate 35%, β-Artemether elaboration 3.9 grams, productive rate 39%.
Detect through HPLC, the purity of above-mentioned gained α-Artemether and β-Artemether is respectively 99.5%, 99.2%.
Claims (8)
1. the method that from the Artemether synthesis mother liquid, prepares Artemether, it is characterized in that: get the Artemether synthesis mother liquid through solid concentrated, dry gained, with upper macroporous resin column behind the organic solvent dissolution, it is 20～70% acetone wash-out with volumetric concentration, thin-layer chromatography detects, and Fractional Collections contains the elutriant of α-Artemether and contains the elutriant of β-Artemether; Reclaim respectively the elutriant of the above-mentioned α of containing-Artemether and contain solvent, filtration in the elutriant of β-Artemether, obtain α-Artemether crude product and β-Artemether crude product, carry out crystallization with adding water behind the dissolve with ethanol respectively again, namely get α-Artemether and β-Artemether.
2. the method that from the Artemether synthesis mother liquid, prepares Artemether according to claim 1, it is characterized in that: get the Artemether synthesis mother liquid through solid concentrated, dry gained, with upper macroporous resin column behind the organic solvent dissolution, it is first 20～70% acetone wash-out with volumetric concentration, thin-layer chromatography detects, and collects the elutriant that contains α-Artemether, is 70～100% acetone wash-outs with volumetric concentration again, thin-layer chromatography detects, and collects the elutriant that contains β-Artemether; Reclaim respectively the elutriant of the above-mentioned α of containing-Artemether and contain solvent, filtration in the elutriant of β-Artemether, obtain α-Artemether crude product and β-Artemether crude product, carry out crystallization with adding water behind the dissolve with ethanol respectively again, namely get α-Artemether and β-Artemether.
3. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 1 and 2, it is characterized in that: the model of described macroporous resin is D101, D102 or AB-8.
4. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 1 and 2, it is characterized in that: described organic solvent is methylene dichloride, methyl alcohol, acetone, ethyl acetate, acetonitrile or ethanol.
5. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 1, it is characterized in that: the flow velocity of liquid is 5～6ml/min when wash-out.
6. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 1, it is characterized in that: the volumetric concentration of described acetone is 40～60%.
7. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 2 is characterized in that: the volumetric concentration of the acetone of using during wash-out α-Artemether is 40～60%.
8. the method for preparing Artemether from the Artemether synthesis mother liquid according to claim 2, it is characterized in that: when collection contained the elutriant of α-Artemether, flow rate of liquid was 5～6ml/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102210782A CN102911183A (en) | 2011-08-03 | 2011-08-03 | Method for preparing artemether from artemether synthetic mother liquor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102210782A CN102911183A (en) | 2011-08-03 | 2011-08-03 | Method for preparing artemether from artemether synthetic mother liquor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102911183A true CN102911183A (en) | 2013-02-06 |
Family
ID=47609784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102210782A Pending CN102911183A (en) | 2011-08-03 | 2011-08-03 | Method for preparing artemether from artemether synthetic mother liquor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102911183A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105699584A (en) * | 2016-02-03 | 2016-06-22 | 昆药集团股份有限公司 | Detection method for artemether related matters |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999033461A1 (en) * | 1997-12-30 | 1999-07-08 | Hauser, Inc. | C-10 carbon-substituted artemisinin-like trioxane compounds having antimalarial, antiproliferative and antitumour activities |
| US6336631B1 (en) * | 1999-07-08 | 2002-01-08 | John K. Volkert | Two-sided puzzle |
| CN101130548A (en) * | 2006-08-25 | 2008-02-27 | 上海诺德生物实业有限公司 | Method for extracting and producing high content arteannuin |
| CN101857599A (en) * | 2009-04-09 | 2010-10-13 | 广州斯威森科技有限公司 | Industrial stereospecific synthesis of beta-artemether by using artemisinin as raw material |
-
2011
- 2011-08-03 CN CN2011102210782A patent/CN102911183A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999033461A1 (en) * | 1997-12-30 | 1999-07-08 | Hauser, Inc. | C-10 carbon-substituted artemisinin-like trioxane compounds having antimalarial, antiproliferative and antitumour activities |
| US6336631B1 (en) * | 1999-07-08 | 2002-01-08 | John K. Volkert | Two-sided puzzle |
| CN101130548A (en) * | 2006-08-25 | 2008-02-27 | 上海诺德生物实业有限公司 | Method for extracting and producing high content arteannuin |
| CN101857599A (en) * | 2009-04-09 | 2010-10-13 | 广州斯威森科技有限公司 | Industrial stereospecific synthesis of beta-artemether by using artemisinin as raw material |
Non-Patent Citations (5)
| Title |
|---|
| M. GABRIËLS，等: "Development of a Reversed-Phase Thin-Layer Chromatographic Method for Artemisinin and Its Derivatives", 《JOURNAL OF CHROMATOGRAPHIC SCIENCE》 * |
| MATTHIAS BOEHM，等: "An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 张仁斌，等: "反相高效液相色谱分离青蒿素及其衍生物", 《药学学报》 * |
| 李英，等: "青蒿素衍生物的合成", 《科学通报》 * |
| 谢笑天，等: "蒿甲醚合成母液中一个新成分的分离和鉴定", 《中草药》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105699584A (en) * | 2016-02-03 | 2016-06-22 | 昆药集团股份有限公司 | Detection method for artemether related matters |
| CN105699584B (en) * | 2016-02-03 | 2018-02-09 | 昆药集团股份有限公司 | A kind of detection method of Artemether related substances |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101134758B (en) | Method for extracting and separating bilobalide A, B, C, J and bilobalide monomer from ginkgo leaf | |
| CN101397284A (en) | Method for extracting and separating paclitaxel and taxones compounds from yew | |
| CN111807932A (en) | Method for extracting and purifying cannabidiol from cannabis sativa | |
| CN105294628A (en) | Method for preparing flavonoid component by separating wild chrysanthemum flower | |
| CN104230858B (en) | A kind of method of separating and purifying taxol from Ramulus et folium taxi cuspidatae or bark | |
| CN101412725B (en) | Method for extracting and separating bilobalide B from ginkgo leaf | |
| CN104829666A (en) | Method for preparing high purity baicalin from radix scutellariae | |
| CN103044442A (en) | Method for separating and purifying GA, GB and bilobalide from folium ginkgo extractive | |
| CN102399259B (en) | Method for separating and purifying liriope spicata saponin B | |
| CN102911183A (en) | Method for preparing artemether from artemether synthetic mother liquor | |
| CN109400566B (en) | Method for extracting and separating high-purity amentoflavone from Selaginella plant | |
| CN108299298B (en) | Efficient extraction method of norisoboldine | |
| CN103554133B (en) | Technology for preparing high-purity tacrolimus | |
| CN101085780B (en) | Preparation method for ginkgolide | |
| CN104211667A (en) | Plant extract applied in taxol preparation and preparation method thereof | |
| CN105820213B (en) | The method for efficiently separating purifying knob not Kangding | |
| CN103145722A (en) | Method for separating and purifying epothilone by high-speed counter-current chromatography | |
| CN103641884B (en) | A kind of method extracting Triptolide 12,13-chlorohydrin in trypterygine leading portion medicinal extract | |
| CN109705182B (en) | Preparation method of nilestriol | |
| CN105061458B (en) | Preparation method of nontoxic high-purity ginkgo total lactones and monomers thereof | |
| CN101701019B (en) | Separation and purification method of ginkgolide A and B monomer | |
| CN102911185B (en) | Method for separating and purifying ginkgolides A, B, C and D and bilobalide from ginkgo leaf extracts | |
| CN105669604A (en) | New method for purifying wild hazel-mushroom taxol through ultrahigh-pressure extraction, biological enzymolysis and countercurrent chromatography | |
| CN105085443A (en) | Method for using Taxus media branches and leaves as raw material to prepare high-purity 10-deacetyl baccatin III | |
| CN102584704B (en) | A kind of polymer microballoon is separated the method preparing geldanamycin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130206 |