- One-pot green synthesis of β-artemether/arteether
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An efficient one pot green synthesis of β-artemether/arteether from artemisinin has been developed using a sodium borohydride-cellulose sulfuric acid (CellSA) catalyst system. The green methodology is high yielding and the catalyst has good recyclability.
- Kumar, Atul,Bishnoi, Ajay Kumar
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- Preparation method of beta-artemether
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The invention belongs to the field of organic chemistry or medicinal chemistry, and particularly relates to a preparation process of beta-artemether, which comprises: (1) adding methanol to a reactioncontainer, and adding dihydroartemisinin through a solid feeding pump to obtain a dihydroartemisinin suspension; (2) feeding and mixing the dihydroartemisinin suspension, an etherifying agent and anacid catalyst according to a volume ratio of 500:95-105:2.5-3.5 to form a reaction system; (3) neutralizing with a sodium bicarbonate solution, and performing refined filtration to obtain refined filtrate; (4) adding the fine filtrate into purified water, adding the purified water while adding the fine filtrate, stirring, and crystallizing; and (5) centrifuging, washing and drying to obtain the beta-artemether. The preparation method is safe and environmentally friendly, isomer impurities can be controlled to the maximum extent, the product purity is 99% or above, automatic equipment can be adopted for continuous production, and the industrial production efficiency is improved.
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Paragraph 0046-0072
(2021/02/13)
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- A process for preparing β - pedic ether process
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The invention discloses a technology for preparing beta-artemether. The technology comprises the following steps: reducing an initial raw material artemisinin in the presence of a reducing agent to generate dihydroartemisinin, and carrying out an etherification reaction on dihydroartemisinin and trimethyl orthoacetate in the presence of a catalyst to prepare beta-artemether. Experiments prove that the technology allows the content of alpha-artemether generated in the methyl etherification reaction to be smaller than 3%, the HPLC purity of the obtained beta-artemether to be improved to above 99.8%, the content of single impurities to be smaller than 0.1% respectively and the quality of the above product to accord with requirements of United States Pharmacopeia; and the total mole yield of the product by artemisinin can reach 95% or above. The technology can avoid tedious intermediate processing links in the prior art, realizes simple-operation low-cost high-yield preparation of highly pure beta-artemether, accords with industrial production demands of beta-artemether, and has industrial application values.
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Paragraph 0023-0024; 0025-0026; 0027-0028
(2018/04/21)
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- Process for preparation of β - pedic methyl ether
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The invention relates to a preparation method of beta-artemether. The preparation method comprises the following steps of: (1) adding a solvent alcohol to dihydroartemisinin to dissolve dihydroartemisinin; (2) reducing the temperature of a solution obtained from the step (1) to 0-5 DEG C, and adding an etherealization reagent; (3) dropping the alcoholic solution of an acid at 0-20 DEG C to a system obtained from the step (2), and reacting at 0-30 DEG C, wherein the pH value of a reaction system is 1-3; (4) separating out solids from the system by adding water to the reaction liquid of the step (3), filtering, and washing the obtained solids by using water to obtain a compound; (5) drying the compound obtained from the step (4) to constant weight at 35-45 DEG C to obtain beta-artemether, wherein the purity of beta-artemether is more than 99%. The preparation method disclosed by the invention effectively inhibits the generation of isomer alpha-artemether in reaction, can enable the etherealization reaction to be mildly carried out and is simple in post-treatment and high in product purity. According to the invention, the purity of all prepared beta-artemether crude products is higher than 99%.
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Paragraph 0061; 0062; 0065; 0066
(2017/08/25)
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- Method for producing artesunate
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The invention relates to a method for producing artesunate. The method is characterized by comprising the following steps: (a) carrying out a reaction: adding dihydroartemisinin into dichloromethane, then, adding methanol and perchloric acid, carrying out the reaction for 10 to 15 minutes, adding anhydrous sodium carbonate to terminate the reaction, and filtering the reaction solution; (b) carrying out concentration: concentrating the filtered reaction solution in a water bath with the temperature of about 55 DEG C; (d) carrying out crystallization: subjecting the concentrated mother liquor to freeze-crystallizing, and carrying out centrifugal filtration, so as to obtain crude crystals; (e) carrying out refining: dissolving the crude crystals with methanol at the temperature of 65 DEG C so as to obtain a saturated solution, carrying out cooling-crystallization, and carrying out centrifugal filtration; and (f) carrying out baking: subjecting the crystals to vacuum drying for 120 minutes at the temperature of 55 DEG C, thereby obtaining a finished product. According to the method, the yield can reach 76% in case of not treating the generated mother liquor, the reaction time is short, energy is saved, and the production cost is reduced.
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Paragraph 0012-0036
(2017/06/06)
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- Synthesis of the antimalarial API artemether in a flow reactor
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The earlier developed flow protocol for stoichiometric reduction of an important biologically derivedpharmaceutical precursor, artemisinin, to dihydroartemisinin was extended to a sequential reaction toproduce one of the final APIs, artemether. A highly active heterogeneous catalyst was found for theetherification reaction. The use of QuadraSil catalyst allows to eliminate one step of reaction workup. Acomparative Life Cycle Assessment of both reactions has shown advantages of the flow process over theoptimized literature batch protocols. Results of LCA highlight the significance of solvents in pharmaceut-icals manufacture and the advantage of flow technology, enabling small solvent inventories to be used.
- Yaseneva, Polina,Plaza, Dorota,Fan, Xiaolei,Loponov, Konstantin,Lapkin, Alexei
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- New method for the synthesis of ether derivatives of artemisinin
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Dihydroartemisinin can be converted to its ether derivatives in good yields by reaction with different alcohols in the presence of a catalytic amount of dodecatungstophosphoric acid hydrate. Easy handling, trouble-free workup by filtration, excellent yields, and very short reaction times are some of the highlights of this protocol. Copyright Taylor & Francis Group, LLC.
- Bora, Pranjal P.,Baruah, Nabajyoti,Bez, Ghanashyam,Barua, Nabin C.
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p. 1218 - 1225
(2012/04/04)
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- A PROCESS FOR PREPARATION OF ETHER DERIVATIVES OF DIHDROARTEMISININ
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The present invention relates to a facile and cost-effective process for the preparation of ether derivatives of dihydroartemisinin. The present invention further enables preparation of pure β-ether derivatives of dihydroartemisinin, commonly known as Artemether, the methyl ether derivative and Arteether, the ethyl ether derivative, which are well-known antimalarial agents without using an organic pro-acid. This invention also discloses a novel epimerisation process for the a-ether derivatives of dihydroartemisinin in β- isomer.
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Page/Page column 8
(2012/04/17)
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- A NOVEL PROCESS FOR THE PREPARATION OF ETHERS OF DIHYDROARTEMISININ
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A process for the preparation of ethers of dihydroartemisinin containing more than 99 % of ? isomer from dihydroartemisinin which comprises: reacting dihydroartemisinin with an alcohol and hydrolysable organic halides as a pro-acid catalyst in the presence of a co-solvent at 0 - 45 °C; diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine; cooling the reaction mass to 0 °C-5 °C and stirring to obtain the solid product; filtering the solid to obtain the ethers of dihydroartemisinin; recrystallizing the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99 % of ? isomer.
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Page/Page column 14
(2009/10/22)
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- An improved manufacturing process for the antimalaria drug coartem. Part I
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Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was re-investigated. The most important factor for obtaining optimal yields is to ensure low levels of contamination of potassium hydroxide in potassium borohydride. Application of a lower reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with acid are further important parameters in guaranteeing a robust process. In the redesign of the conversion of dihydroartemisinin to artemether, the yield was increased, and dichloromethane was replaced by the ecologically friendlier methyl acetate. A robust manufacturing process for artemether is now at hand, allowing the production of this important medicine reliably and in good quality and yield. & 2007 American Chemical Society.
- Boehm, Matthias,Fuenfschilling, Peter C.,Krieger, Matthias,Kuesters, Ernst,Struber, Fritz
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p. 336 - 340
(2012/12/31)
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- Process for the preparation of arteethers from dihydroartemisinin
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The invention relates to an improved process for the preparation of arteether. The process comprises dissolving dihydroartemisinin in dry ethanol, adding a solid acid catalyst with trialkylorthoformate in the reaction mixture, stirring the reaction mixture at room temperature, adding H2O to the reaction mixture, extracting the reaction product with a non-polar organic solvent, and drying the solvent over anhydrous sodium sulphate and evaporating the solvent to obtain pure arteether.
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Page column 4
(2008/06/13)
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- A one-pot conversion of artemisinin to its ether derivatives
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A one-pot preparation of artemether, arteether and related antimalarial compounds from artemisinin, using NaBH4/Amberlyst-15, is reported.
- Singh, Chandan,Tiwari, Pallavi
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p. 7235 - 7237
(2007/10/03)
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- Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 2. Stereospecificity of the ether side chain
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A new series of hydrolytically stable and water-soluble dihydroartemisinin derivatives with optically active side chains was prepared as potential antimalarial agents. This was an effort to prepare compounds with activity superior to that of artelinic acid and to examine the impact of the stereospecificity of the introduced alkyl side chain on biological properties. The ester derivatives possess superior in vitro activity to artemisinin, artemether, and arteether against two strains of Plasmodium falciparum (D-6 and W-2); however, conversion of the esters to their corresponding acids drastically reduces their antimalarial activity. None of the new acids possess in vitro antimalarial activity superior to that of artelinic acid. Although there appears to be limited stereospecificity for antimalarial activity among the acids (7a-d) tested, significant differences in antimalarial activity was seen among the esters.
- Lin,Lee,Klayman
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p. 1249 - 1252
(2007/10/02)
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