CN103570740A - Preparation process of artemether - Google Patents
Preparation process of artemether Download PDFInfo
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- CN103570740A CN103570740A CN201310563637.7A CN201310563637A CN103570740A CN 103570740 A CN103570740 A CN 103570740A CN 201310563637 A CN201310563637 A CN 201310563637A CN 103570740 A CN103570740 A CN 103570740A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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Abstract
The invention relates to a process for preparing high-purity beta-artemether, and aims to provide a preparation process of artemether, and the preparation process has the advantages of easiness in technological operation, low cost and high yield. The preparation process of the artemether comprises the following steps: a, etherifying, namely adding dihydroartemisinin into an ester solvent to perform etherification reaction under the action of a catalyst; b, concentrating, namely concentrating and drying the etherification product to obtain the product. The preparation process is simple and easy to operate and is suitable for industrialization; the reaction solvent and an etherifying agent in the entire process are the same solvent, namely the ester solvent, so that the control over the industrial production is more facilitated, and the recovery and reuse of the solvent are also facilitated; the yield of the beta-artemether in the prepared product reaches over 95 percent, the raw material is greatly saved, and the production cost is reduced; the time of the entire synthesis reaction is only 1-2 hours, so that the production period is short; the reaction can be excellently performed under the room temperature condition without freezing treatment, so that energy is saved, and industrial production is also facilitated.
Description
Technical field
The present invention relates to a kind of Artemether preparation technology, be specifically related to a kind of technique of preparing high-purity beta-Artemether.
Background technology
Artemisinin is that artemisinine is the sesquiterpene lactones medicine that has peroxy-radical extracting from the blue or green punt-pole of Chinese medicine, is the specifics of the malaria that causes for the treatment of plasmodium falciparum.The derivative of Artemisinin mainly contains Artesunate, Artemether and Dihydroartemisinin etc.
And Artemether (English name Artemether) claims again first hydrogen reduction Artemisinin or Artemtherin, odorless, mildly bitter flavor, is very easily dissolved in acetone or chloroform, easily molten in ethanol or vinyl acetic monomer, water-soluble hardly, and fusing point is 86～90 ℃.Artemether is the specifics by the various critical malaria patients for the treatment of of Chinese independent research and rescue encephalic malaria patient, have that drug effect is fast, good effect, low toxicity, easy to use, antimalarial active is high, with chloroquine without advantages such as cross-resistances, and because its solubleness in oil is greater than Artemisinin, be beneficial to preparation, becoming is the first-selected antimalarial drug that the World Health Organization (WHO) is recommended, and by WHO, is listed in essential drugs core catalogue.
The molecular formula of Artemether is C
16h
26o
5, be divided into two epimers of α-Artemether and β-Artemether, and what have antimalarial active is mainly β-Artemether, therefore be mainly to carry out for β-Artemether for the study on the synthesis of Artemether.The molecular structural formula of α-Artemether and β-Artemether is as follows respectively:
The method of early stage synthetic β-Artemether has: under room temperature, dihydroarteannuin (claiming again Reducing arteannuim) and methyl alcohol are carried out to etherification reaction under the catalysis of boron trifluoride diethyl etherate, reaction finishes with column chromatography, to carry out separation afterwards, obtain β-Artemether crude product, yield is only 59.5%, synthetic > > referring to < < artemisinin derivative, Li Ying etc., < < Science Bulletin > >, 1979, 24 (14), 667-9.This kind of method not only yield of β-Artemether is low, and complicated operation, is not suitable for and suitability for industrialized production.
For further improving yield, researchist has carried out some improvement for the synthesis technique of Artemether, as the synthesising process research > > (Li Xuefang etc. of < < β-Artemether, < < chemistry and biotechnology > >, 2009, 26 (6), 54-8): by dihydroarteannuin and methyl alcohol under the catalysis of trifluoroacetic acid, in dichloromethane solvent, at 40 ℃, react, obtaining yield is 70%, purity is β-Artemether of 99.3%.The yield of visible this kind of method also, not as people's will, causes the waste of Artemisinin raw material.The patent that and for example application number is 200910038509.4 " be take Artemisinin as primary industry stereospecific synthesis of beta-artemether " provides a kind of utilization in methylene dichloride alkaline aqueous solution system, using sodium borohydride as reductive agent, tert.-butoxy Al catalysts, the dihydroarteannuin that reduction obtains, separate water, add methyl alcohol and sodium pyrosulfate, aluminum perchlorate, nickelous perchlorates etc. are as the catalyzer of methyl-etherified reaction, room temperature reaction 2h obtains β-Artemether productive rate and is up to 85%, Artemether overall yield is up to 93.5%, and temperature of reaction must be controlled at-10-10 ℃ in reaction process.This method complicated operation, need freezing reaction, and in the product obtaining, the content of β-Artemether is still not high.
Summary of the invention
For the lower weak point of yield in above-mentioned prior art, the object of the present invention is to provide the Artemether preparation technology that a kind of technological operation is simple, cost is low, yield is high.
For achieving the above object, the technical solution used in the present invention is: a kind of Artemether preparation technology comprises step:
A, etherificate: dihydroarteannuin is added and in esters solvent, under catalyst action, carries out etherification reaction;
B, concentrated: etherification product concentrate drying is obtained to product.
The organic solvent that contains ester bond that esters solvent is commonly used, as sec-butyl acetate, ethyl butyrate, ethyl acetate, isobutyl acetate, Phenylethyl ethanoate, butyl formate, dinoctyl phthalate etc.The present invention prepare favorite in, these esters solvents are reaction solvent, are again etherifying agents.
Further preferred, in described step a, esters solvent is a kind of in methyl acetate, ethyl acetate, methylcarbonate.Methylcarbonate preferably wherein.
Further, in described step a, catalyzer is a kind of in boron trifluoride methyl ether, sulfuric acid, hydrochloric acid.Boron trifluoride methyl ether preferably wherein.
Further, in described step a, dihydroarteannuin, esters solvent, catalyzer three's mol ratio is 1:34-51:0.025-0.5.
Further, in described step a, the temperature of reaction of etherification reaction is normal temperature.So-called normal temperature is the temperature of 15 ℃ to 25 ℃, and this temperature is also more suitable for suitability for industrialized production.
Further, in described step a, the reaction times of etherification reaction is 1-2h.
Further, in described step a, etherification reaction carries out enrichment step after pH value of solution being adjusted to 7 ± 0.1 after finishing again.
Further, in described step a, the solution for regulator solution pH value is saturated sodium bicarbonate aqueous solution.
Further, described step b concentrate drying gained Artemether crude product carries out recrystallization with organic solvent, and the crystal drying obtaining is product.That is to say that the Artemether crude product obtaining after step b concentrate drying is just the finished product again after recrystallization.
Further, simmer down to concentrating under reduced pressure in described step b, is dried as vacuum-drying, and concentrated and dry temperature is not all higher than 50 ℃.
In technique scheme, the consumption of each component is the optimum feed stock ratio that participates in reaction, but the variation that those skilled in the art can instruction according to the present invention be equal to.For example: because the parameter that the error of industrial production itself causes changes with technical scheme of the present invention, be equal to.
Artemether preparation technology provided by the invention has the following advantages:
1, preparation technology is simple to operation, is applicable to industrialization, and in whole technique, reaction solvent and etherifying agent are same solvent, i.e. esters solvent, and the control of the suitability for industrialized production of being more convenient for like this, is also beneficial to the recovery of solvent;
2, the yield of preparing β-Artemether in the product of gained reaches more than 95%, has saved dramatically raw material, has reduced production cost;
3, the time of whole building-up reactions is only 1-2h, with short production cycle, and only needs just can well carry out at ambient temperature, does not need freezing treatment, has saved the energy, is also more conducive to suitability for industrialized production.
Embodiment
For those skilled in the art are known and technical scheme clearly of the present invention more, spy provides preferred embodiment below, but technological thought of the present invention is not limited to following examples.
Embodiment mono-
Take 100g dihydroarteannuin, drop in 2000ml three-necked bottle, under stirring, add successively 1000ml methylcarbonate, 5ml boron trifluoride methyl ether.Under normal temperature, react 2 hours, sampling is carried out thin-layer chromatography (TLC) and is detected without dihydroarteannuin spot, and dihydroarteannuin reacts completely.Add saturated sodium bicarbonate liquid to adjust pH value of solution to 7.At 50 ℃, under vacuum condition, reaction solution is concentrated into dryly, obtain Artemether coarse-grain 98.23g.Artemether coarse-grain is with after dissolve with methanol, and low temperature crystallization, is dried and obtains Artemether product in 50 ℃, contains after testing β-Artemether 95.16g in counting yield.
Embodiment bis-
Take 100g dihydroarteannuin, drop in 2000ml three-necked bottle, under stirring, add successively 1500ml methylcarbonate, 5ml boron trifluoride methyl ether.Under normal temperature, react 2 hours, sampling TLC detects without dihydroarteannuin spot.Add saturated sodium bicarbonate liquid to adjust pH value of solution to 7.At 50 ℃, under vacuum condition, reaction solution is concentrated into dryly, obtain Artemether coarse-grain 98.46g.Artemether coarse-grain is with after dissolve with methanol, and low temperature crystallization, is dried and obtains Artemether product in 50 ℃, contains after testing β-Artemether 95.32g in counting yield.
Embodiment tri-
Take 100g dihydroarteannuin, drop in 2000ml three-necked bottle, under stirring, add successively 1000ml ethyl acetate, 10ml boron trifluoride methyl ether.Under normal temperature, react 1.5 hours, sampling TLC detects without dihydroarteannuin spot.Add saturated sodium bicarbonate liquid to adjust pH value of solution to 7.At 50 ℃, under vacuum condition, reaction solution is concentrated into dryly, obtain Artemether coarse-grain 98.36g.Artemether coarse-grain is with after dissolve with methanol, and low temperature crystallization, is dried and obtains Artemether product in 50 ℃, contains after testing β-Artemether 95.25g in counting yield.
Embodiment tetra-
Take 100g dihydroarteannuin, drop in 2000ml three-necked bottle, under stirring, add successively 1500ml methyl acetate, 10ml boron trifluoride methyl ether.Under normal temperature, react 2 hours, sampling TLC detects without dihydroarteannuin spot.Add saturated sodium bicarbonate liquid to adjust pH value of solution to 7.At 50 ℃, under vacuum condition, reaction solution is concentrated into dryly, obtain Artemether coarse-grain 98.38g.Artemether coarse-grain is with after dissolve with methanol, and low temperature crystallization, is dried and obtains Artemether product in 50 ℃, contains after testing β-Artemether 95.28g in counting yield.
Claims (10)
1. an Artemether preparation technology, is characterized in that: comprise step:
A, etherificate: dihydroarteannuin is added and in esters solvent, under catalyst action, carries out etherification reaction;
B, concentrated: etherification product concentrate drying is obtained to product.
2. Artemether preparation technology according to claim 1, is characterized in that: in described step a, esters solvent is a kind of in methyl acetate, ethyl acetate, methylcarbonate.
3. Artemether preparation technology according to claim 1, is characterized in that: in described step a, catalyzer is a kind of in boron trifluoride methyl ether, sulfuric acid, hydrochloric acid.
4. Artemether preparation technology according to claim 1, is characterized in that: in described step a, dihydroarteannuin, esters solvent, catalyzer three's mol ratio is 1:34-51:0.025-0.5.
5. Artemether preparation technology according to claim 1, is characterized in that: in described step a, the temperature of reaction of etherification reaction is normal temperature.
6. Artemether preparation technology according to claim 1, is characterized in that: in described step a, the reaction times of etherification reaction is 1-2h.
7. Artemether preparation technology according to claim 1, is characterized in that: in described step a, etherification reaction carries out enrichment step after pH value of solution being adjusted to 7 ± 0.1 after finishing again.
8. Artemether preparation technology according to claim 7, is characterized in that: the solution for regulator solution pH value in described step a is saturated sodium bicarbonate aqueous solution.
9. Artemether preparation technology according to claim 1, is characterized in that: described step b concentrate drying gained Artemether crude product carries out recrystallization with organic solvent, and the crystal drying obtaining is product.
10. Artemether preparation technology according to claim 1, is characterized in that: simmer down to concentrating under reduced pressure in described step b, be dried as vacuum-drying, and concentrated and dry temperature is not all higher than 50 ℃.
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| CN201310563637.7A CN103570740A (en) | 2013-11-12 | 2013-11-12 | Preparation process of artemether |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110835349A (en) * | 2019-11-12 | 2020-02-25 | 张家港威胜生物医药有限公司 | Method for preparing α -arteether bulk drug by one-pot method |
| CN112358488A (en) * | 2020-11-05 | 2021-02-12 | 张家港威胜生物医药有限公司 | Preparation method of beta-artemether |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6346631B1 (en) * | 2000-03-24 | 2002-02-12 | Council Of Scientific And Industrial Research | Process for the preparation of arteethers from dihydroartemisinin |
| 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 |
| WO2013040750A1 (en) * | 2011-09-20 | 2013-03-28 | 上海迪赛诺药业有限公司 | Method for preparing β-artemether |
-
2013
- 2013-11-12 CN CN201310563637.7A patent/CN103570740A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6346631B1 (en) * | 2000-03-24 | 2002-02-12 | Council Of Scientific And Industrial Research | Process for the preparation of arteethers from dihydroartemisinin |
| 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 |
| WO2013040750A1 (en) * | 2011-09-20 | 2013-03-28 | 上海迪赛诺药业有限公司 | Method for preparing β-artemether |
Non-Patent Citations (2)
| Title |
|---|
| MATTHIAS BOEHM，等: "An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 未公开: "PROCESSES FOR PREPARING ETHER DERIVATIVES OF DIHYDRO-ARTEMESININ", 《IP.COM JOURNAL》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110835349A (en) * | 2019-11-12 | 2020-02-25 | 张家港威胜生物医药有限公司 | Method for preparing α -arteether bulk drug by one-pot method |
| CN112358488A (en) * | 2020-11-05 | 2021-02-12 | 张家港威胜生物医药有限公司 | Preparation method of beta-artemether |
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Application publication date: 20140212 |