CN103113385A - Simple mass production process of preparing artemisinin 10-position ether derivative by using dihydroartemisinin as raw material - Google Patents
Simple mass production process of preparing artemisinin 10-position ether derivative by using dihydroartemisinin as raw material Download PDFInfo
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Abstract
The invention discloses a simple mass production process of preparing artemisinin 10-position ether derivative by using dihydroartemisinin as a raw material. The process comprises the steps of: controlling the temperature to be between 0 and 10 DEG C and dropwise adding reaction alcohol reagent in a dried low-polarity solvent system to dilute an acid catalyst, reacting at the temperature of 30-70 DEG C, and performing thin-layer chromatography detection on the reaction process; respectively adding tap water of which the volume is 1/2 of the solvent, 5 percent sodium carbonate solution and deionized water to extract after the reaction is finished; drying an organic phase for 2 hours by using anhydrous sodium sulfate; concentrating until the volume of the solvent is about 4 times that of the input amount of dihydroartemisinin; stirring and deeply cooling to -15 DEG C to crystallize to obtain a coarse crystal; dissolving the coarse crystal by 6 times of absolute methanol or ethanol and equal 0.01 percent hydrochloric acid; and cooling at about 0 DEG C to crystallize to obtain qualified beta-artemisinin. The process is a single-reaction kettle process, convenient to operate, environment-friendly and controllable, and suitable for mass production application of artemisinin 10-position ether derivative.
Description
Technical field
The present invention relates to 10 ethers special efficacy anti-malarial derivative preparations of Artemisinin, be specifically related to prepare take dihydroarteannuin as raw material the simple large new process of production of the ether derivatives such as Artemether, arteether.
Background technology
Malaria is primary three large one of third world countries' human health diseases that endanger of eliminating of World Health Organization's 21 century, and other two large diseases are respectively pulmonary tuberculosis and acquired immune deficiency syndrome (AIDS).Malaria is a transmissible disease of subtropical and tropical zones, is endangering the healthy of 2,000,000,000 populations; Pernicious malaria causes people more than 400,000,000 to infect and approximately 3,000,000 people (most children of being) death every year, has particularly become No.1 killer in Africa.Before Artemisinin was found, main anti-malaria medicaments was that ledger bark extracts series natural quinine hydrochloric acid or the Sulfates that obtains, and the chloroquini phosphas, the sulfuric acid PIPERAQUINE that synthesized afterwards.The sixties in last century, Zhou premier accesses country in Southeast Asia Vietnam that malaria is spread unchecked, for supporting the neighbour scientist of the Chinese Academy of Medical Sciences Effect of Anti malaria specific medicament of calling, one have state secret character, code name starts for the plan of " 523 project " for this reason.
By slaughter cry of a deer and the antimalarial agent Artemisinin researched and developed together of her colleagues be exactly the achievement of this plan.From eighties of last century since the end of the nineties, Artemisinin has been saved countless life as the first-line drug for the treatment of malaria, and wherein major part is women and the children that live in the poverty-stricken area in Africa, South America and South East Asia.
Artemisinin is the most effective anti-malarial natural drug of finding at present, but due to its structural singularity, there are the shortcomings such as unstable, that solvability is looked into when medication, the countries in the world scientists has been invented hydro-reduction derivative that its dihydroarteannuin is representative, 10-position ether derivative and the bit esterified derivative of the 10-take Artesunate as representative take Artemether, arteether as representative in succession for this reason, these derivatives actives are stronger than Artemisinin activity, and all are used widely clinically.Wherein Artemisinin 10-position ethers is one of active best artemisinin derivative, and its antimalarial effect is 6 times of left and right of its lead compound Artemisinin.
10-ether derivative of Artemisinin synthetic mainly contains two kinds of techniques, and the one, first hydro-reduction Artemisinin obtains dihydroarteannuin, further ether derivatives such as synthetic Artemether, arteether again after the washing drying.this route reaction raw material is dihydroarteannuin and alcohol, solvent comprises acetone, ethylene dichloride, ethyl acetate, toluene etc., catalyzer has sulfuric acid, hydrogenchloride, tosic acid, methylsulfonic acid, boron trifluoride diethyl etherate, trifluoroacetic acid, trimethylchlorosilane with, (the Rawalnath such as hydrosulfate and strong acid type resin, S.R., Kanji, K.N., Nilkanth, F.P., Indian Pat.Appl., 2006, 15pp.USA.IP.com Journal, 2007, 7 (9B): 12.Anon.USA.IP.com Journal2008, 8 (6B): 10.Jain D.C, Bhakuni R.S, Saxena S, kumar, S and Vishwakarma, R.A.U.S.Pat.No.6, 346, 631, G.B.Application no0007261.1and German application no10014669.4. Peng Xue east, the .CN101857599A such as Zhao Jinzhao).The water that generates due to reaction can affect the derivative generation of two hydrogen ethers, has bibliographical information also to add the siccative such as ortho-formiate class, molecular sieve and anhydrous sodium sulphate also to comprise Kalhapure, V.K., Arora, V., Prasad, A.Indian Pat.Appl., 2008,10.Bhakuni, R.S.; Jain D.C and Sharma R.P. Indian.J.Chemistry, 1995,34B:529-30.Jain, D.C., Bhakuni, R.S., Saxena, S., Council of Scientific and Industrial Research, India, 2004,13.).the second operational path is that the single reaction still directly prepares the Artemisinin ether derivative from Artemisinin again, its flow process comprises Artemisinin is reduced to dihydroarteannuin, continue again to add alcohols feedstock and catalyzer to continue reaction in the dihydroarteannuin reaction system, obtain Artemisinin ether (Singh, C., Tiwari, P.Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry (2002), 41B (10), 2185-2186.Do, H.N., Ha N.Tap Chi Duoc Hoc, 2001, (7): 7-9.Singh, C., TiwariP. Council of Scientific and Industrial Research, Indian, 2003, 9pp.Singh, C.Tiwari, P. Council of Scientific and Industrial Research, Indian, 2003, 17pp.).Above-mentioned route technique obtains the ethers artemisinin derivative and contains α and two kinds of configurations of β, and productive rate 70～91% does not wait, and wherein α-Artemisinin ether: β-Artemisinin ether is 30: 70～20: 80.Its main separation method finally obtains pure β-Artemisinin ether derivative productive rate between 50～78% for extraction, crystallization recrystallization and column chromatography.
The preparation method of 10 ether derivatives of the above Artemisinin, thus exist that reaction time consumption is long, the aftertreatment flow process complicated, stereoselectivity is low, impurity is many, overall yield is not high causes that cost is higher to be reached shortcomings such as environment are unfriendly.The feature part that the present invention is different from aforesaid method is:
(1) take dihydroarteannuin and pure as semi-synthetic raw material, add the reaction system of low polar solvent;
(2) catalyst for etherification of the present invention is superpower solid acid, methylsulfonic acid, trifluoromethane sulfonic acid, antimony pentafluoride and boron tribromide etc.;
(3) because dihydroarteannuin in this system is stable, temperature of reaction of the present invention can be controlled in 30～70 ℃, but higher temperature fast reaction speed;
(4) last handling process of the present invention is simple, after extraction and being washed to neutrality, directly is concentrated in crystallization recrystallization in reaction solvent or methyl alcohol, can obtain qualified β-Artemisinin ether;
(5) with respect to one kettle way, the present invention obtains reaction to react after dihydroarteannuin separates again, and can avoid solvent, each step solvent is all recyclable, and the use of minimizing organic solvent, be beneficial to and guarantee the healthy and safe of operator, environmental protection more.This working of an invention will be huge propelling to the Artemisinin ether derivative industry of China, promote greatly the integral level of China's Artemisinin industry to improve, and make that the competition in the Artemisinin field continues the state of remaining ahead in following and India.
Summary of the invention
The key problem that the present invention need to solve is to improve productive rate, especially the chiral isomer α of 10 ether derivatives of semi-synthetic Artemisinin and the ratio of β-Artemisinin ether take dihydroarteannuin as raw material, and the better β of drug activity-Artemisinin ether is had comparative advantage.Adopt suitable equipment and process, can reach easy and simple to handle, be easy to health maintenance, greatly reduce the production cost of β-Artemisinin ether derivative simultaneously.Concrete steps are as follows:
1, Artemisinin is placed in the enamel reaction still of jacketed, stirring, add dihydroarteannuin, the mixed solvent of a kind of or two or more solvents such as hexanaphthene, normal hexane, sherwood oil, isopropyl ether, chloroform that adds while stirring 10～20 times of volumes is with the complete dispersion of dihydroarteannuin;
2, stir the methyl alcohol that adds above-mentioned quantity of solvent 5%～10% in solvent tank or ethanol etc. at a band, be cooled to an acidic catalysts of the about 5 ℃ above-mentioned quantity of solvent 0.1%～2.0% of dropping, stirring and evenly mixing is standby;
The enamel reaction still that 3, will add dihydroarteannuin is cooled to 0～10 ℃, the above-mentioned acid alcohol mixed system of agitation and dropping, and approximately 30min dropwises, 30～70 ℃ of reactions that heat up, thin-layer chromatography is followed the tracks of dihydroarteannuin and is less than 1%, is considered as reaction and completes;
4, reaction solution is cooled to room temperature, respectively with the tap water of 1/2 solvent volume, 5% sodium carbonate solution and deionized water extraction, in and the removal of impurity, organic phase is with anhydrous sodium sulfate drying 2h, reconcentration to solvent is 4 times of left and right volumes of dihydroarteannuin input amount, and stirring and the degree of depth are cooled to-15 ℃ of crystallizations and obtain coarse-grain;
5, coarse-grain adds 0.01% dissolving with hydrochloric acid with 6 times of anhydrous methanols or ethanol etc., and at 0 ℃ of left and right crystallisation by cooling, obtains qualified β-Artemisinin ether.
The present invention adopts single reaction still method directly by 10 ether derivatives of the semi-synthetic β-Artemisinin of dihydroarteannuin, and stepwise reaction can be recycled organic solvent fully, thereby reduces the pollutent possible to environment.Single configuration β-Artemisinin ether derivative productivity ratio bibliographical information technique is higher, greatly improves chemical Atom economy, reduces energy consumption, and low-carbon (LC), efficient is suitable for industrialized production.
Description of drawings
Fig. 1 is 10 ether derivative building-up reactions formulas of Artemisinin
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Embodiment 1
Take dihydroarteannuin 25.0kg in the jacketed enamel reaction still, add dry normal hexane 400.0L, stirring at room is disperseed.Add 40L methyl alcohol in a band stirring solvent tank, be cooled to 5 ℃ of left and right and slowly add the 0.5L trifluoromethane sulfonic acid, stirring and evenly mixing is as reaction reagent A; Freezing plant is controlled in enamel reaction still 0 ℃ of temperature, adds above-mentioned reaction reagent A in 30min, then temperature control is in 35 ℃ of reactions, and thin layer is monitored and o'clock is considered as reaction less than 1% to the dihydroarteannuin raw material and completes.Reactor is cooled to room temperature, tap water, 5% sodium carbonate solution and deionized water with 1/2 solvent volume extracts respectively, obtain organic phase with anhydrous sodium sulfate drying 2h, change in the crystallizer that reclaims with condensation, approximately remain the 160L solvent in being evaporated to below 50 ℃, stirring and the degree of depth are cooled to-15 ℃ of crystallizations, obtain Powdered white Artemether coarse-grain.Crude product is added 0.01% hydrochloric acid heating for dissolving with 6 times of anhydrous methanols, and 0 ℃ of left and right cooling and stirring crystallization, obtain qualified β-Artemether 21.67kg, productive rate counts 82.5% with dihydroarteannuin, the HPLC detection level is greater than 99.0%, related substances, and α-Artemether is less than 0.1%, dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.
Embodiment 2
Take dihydroarteannuin 25.0kg in the jacketed enamel reaction still, add dry sherwood oil 400.0L, stirring at room is disperseed.Add 40L ethanol in a band stirring solvent tank, be cooled to 5 ℃ of left and right and slowly add the 1.0kg solid super-strong acid, stirring and dissolving is as reaction reagent B; Freezing plant is controlled in enamel reaction still 5 ℃ of temperature, adds above-mentioned reaction reagent B in 30min, then temperature control is in 45 ℃ of reactions, and thin layer is monitored and o'clock is considered as reaction less than 1% to the dihydroarteannuin raw material and completes.Reactor is cooled to room temperature, the solids removed by filtration super acids, again respectively with the tap water of 1/2 solvent volume, 5% sodium carbonate solution and deionized water extraction, obtain organic phase with anhydrous sodium sulfate drying 2h, change in the crystallizer that reclaims with condensation, approximately remain the 180L solvent in being evaporated to below 60 ℃, stirring and the degree of depth are cooled to-15 ℃ of crystallizations, obtain Powdered white arteether coarse-grain.Crude product is added 0.01% hydrochloric acid heating for dissolving with 6 times of dehydrated alcohols, and 0 ℃ of left and right cooling and stirring crystallization, obtain qualified β-arteether 24.38kg, productive rate counts 88.8% with dihydroarteannuin, the HPLC detection level is greater than 99.0%, related substances, and α-arteether is less than 0.1%, dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.
Embodiment 3
Take dihydroarteannuin 250g in the jacketed enamel reaction still, add dry chloroform 2.5L, the stirring at room dissolving.Add the 0.4L n-propyl alcohol in a band stirring solvent tank, be cooled to 5 ℃ of left and right and slowly add the 10mL boron tribromide, stirring and dissolving is as reaction reagent C; Freezing plant is controlled in enamel reaction still 5 ℃ of temperature, adds above-mentioned reaction reagent C in 30min, then temperature control is in 55 ℃ of reactions, and thin layer is monitored and o'clock is considered as reaction less than 1% to the dihydroarteannuin raw material and completes.Reactor is cooled to room temperature, tap water, 5% sodium carbonate solution and deionized water with 1/2 solvent volume extracts respectively, obtain organic phase with anhydrous sodium sulfate drying 2h, change in the crystallizer that reclaims with condensation, approximately remain the 1500mL solvent in being evaporated to below 70 ℃, stirring and the degree of depth are cooled to-15 ℃ of crystallizations, obtain Powdered faint yellow wormwood artemisia propyl ether coarse-grain.Crude product is added 0.01% hydrochloric acid heating for dissolving with 10 times of anhydrous n-propyl alcohols, and 0 ℃ of left and right cooling and stirring crystallization, obtain qualified β-wormwood artemisia propyl ether 246.8g, productive rate counts 87.1% with dihydroarteannuin, the HPLC detection level is greater than 99.0%, related substances, and α-wormwood artemisia propyl ether is less than 0.1%, dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.
Embodiment 4
Take dihydroarteannuin 250g in the jacketed enamel reaction still, add dry hexanaphthene 3.5L, the stirring at room dissolving.Add the 0.4L anhydrous methanol in a band stirring solvent tank, be cooled to 5 ℃ of left and right and slowly add the 5.0g antimony pentafluoride, stirring and dissolving is as reaction reagent D; Freezing plant is controlled in enamel reaction still 5 ℃ of temperature, adds above-mentioned reaction reagent D in 30min, then temperature control is in 60 ℃ of reactions, and thin layer is monitored and o'clock is considered as reaction less than 1% to the dihydroarteannuin raw material and completes.Reactor is cooled to room temperature, tap water, 5% sodium carbonate solution and deionized water with 1/2 solvent volume extracts respectively, obtain organic phase with anhydrous sodium sulfate drying 2h, change in the crystallizer that reclaims with condensation, approximately remain the 1500mL solvent in being evaporated to below 60 ℃, stirring and the degree of depth are cooled to-15 ℃ of crystallizations, obtain Powdered white Artemether coarse-grain.Crude product is added 0.01% hydrochloric acid heating for dissolving with 10 times of anhydrous methanols, and 0 ℃ of left and right cooling and stirring crystallization, obtain qualified β-Artemether 226.3g, productive rate counts 86.3% with dihydroarteannuin, the HPLC detection level is greater than 99.0%, related substances, and α-Artemether is less than 0.1%, dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.
Claims (7)
1. a method for preparing 10 ether derivatives of Artemisinin is characterized by, and its starting raw material is dihydroarteannuin and corresponding alcohol, and order of addition(of ingredients) is for successively adding dihydroarteannuin, reaction solvent, acid alcohol mixed system.
2. require described method according to right 1, it is characterized in that adding the low polar aprotic solvent of 10～20 times of volumes of dihydroarteannuin quality in the enamel reaction still that dihydroarteannuin is housed, comprise hexanaphthene, normal hexane, trichloromethane and sherwood oil etc.
3. require described method according to right 1, it is characterized in that catalyzer first dilutes with the alcohols reaction reagent, and control temperature at 5 ℃, then drop to enamel reaction still in 0 ℃～10 ℃.
4. according to right 1,2,3 require described method, it is characterized in that catalyzer comprises trifluoromethane sulfonic acid, methylsulfonic acid, antimony pentafluoride and boron tribromide etc., and its consumption is 0.1%～2% of solvent.
5. according to right 1,2,3,4 require described method, and the dihydroarteannuin etherification reaction is monitored with simple thin-layer chromatography, and Determination of dihydroartemisinin can be considered reaction and completes lower than 1% reference substance point color.
6. according to right 1,2,3,4,5 require described method, and reaction solution is cooled to room temperature, respectively with the tap water of 1/2 solvent volume, 5% sodium carbonate solution and deionized water extraction, in and the removal of impurity, organic phase is with anhydrous sodium sulfate drying 2h, and reconcentration to solvent is 4 times of left and right volumes of dihydroarteannuin input amount, and stirring and the degree of depth are cooled to-15 ℃ of crystallizations and obtain coarse-grain.
7. according to right 1,2,3,4,5,6 require described method, and coarse-grain adds 0.01% dissolving with hydrochloric acid with 6 times of anhydrous methanols or ethanol etc., and at 0 ℃ of left and right crystallisation by cooling, obtains qualified β-Artemisinin ether.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
| CN1106012A (en) * | 1994-01-28 | 1995-08-02 | 中信技术公司 | Improved method for preparation of dihydroartemisin ether derivants |
| WO2009109989A1 (en) * | 2008-01-21 | 2009-09-11 | Calyx Chemicals And Pharmaceuticals Ltd. | A novel process for the preparation of ethers of dihydroartemisinin |
| CN102731523A (en) * | 2012-07-10 | 2012-10-17 | 刘志强 | Preparation method of beta-artemether |
| CN102887907A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | New process for preparing beta-arteether by single reaction kettle method by taking artemisinin as raw material |
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- 2013-01-24 CN CN2013100279320A patent/CN103113385A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
| CN1106012A (en) * | 1994-01-28 | 1995-08-02 | 中信技术公司 | Improved method for preparation of dihydroartemisin ether derivants |
| WO2009109989A1 (en) * | 2008-01-21 | 2009-09-11 | Calyx Chemicals And Pharmaceuticals Ltd. | A novel process for the preparation of ethers of dihydroartemisinin |
| CN102887907A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | New process for preparing beta-arteether by single reaction kettle method by taking artemisinin as raw material |
| CN102731523A (en) * | 2012-07-10 | 2012-10-17 | 刘志强 | Preparation method of beta-artemether |
Non-Patent Citations (1)
| Title |
|---|
| 李雪芳 等: "β-蒿甲醚的合成工艺研究", 《化学与生物工程》 * |
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Application publication date: 20130522 |