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    药物详细合成路线

    Name beta-Arteether;Artemotil;Arteether;SM-227;E MAL;Artecef
    Chemical Name (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-Ethoxy-3,6,9-trimethyldecahydro-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin
          beta-Dihydroquinghaosu ethyl ether
          beta-Dihydroartemisin ethyl ether
    CAS 75887-54-6
    Related CAS 159510-58-4 (deleted CAS)
    Formula C17H28O5
    Structure
    Formula Weight 312.40971
    Stage 上市-2000
    Company Shanghai Institute Materia Medica (Originator), Artecef (Not Determined), Central Drug Research Institute (Not Determined), Themis Chemicals (Codevelopment)
    Activity/Mechanism ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases
    Syn. Route 3
    Route 1
    reduction of artemisinin (i) with sodium borohydride provides dihydroartemisinin (ii) (1-5). subsequent treatment of hemiacetal (ii) with ethanol in the presence of acid catalysts, such as bf3?et2o (1), clsime3 (2), p tsoh (6-8), alcl3 (7, 8) or cation-exchange resins (3, 7, 8) gives rise to the target beta-ethoxy acetal as the major diastereoisomer. alternatively, dihydroartemisinin (ii) is first dehydrated to the enol ether (iii) employing p2o5 in ch2cl2. addition of etoh to (iii) in the presence of pph3?hbr then produces a mixture of the target compound and its 11-alpha epimer (iv), along with minor amounts of their 12-alpha ethoxy analogues (4). the analogous synthesis employing eto2h or eto3h yields the corresponding 11-deuterium or 11-tritium labelled compounds (9).
    List of intermediates No.
    2-(4-methoxyphenyl)acetic acid; p-methoxyphenyl formate; homoanisic acid; p-methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid (i)
    (e)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal (ii)
    Reference 1:
        pu, y.m.; ziffer, h.; diastereofacial additions to a beta-substituted glycal, anhydrodihydroartemisinin. heterocycles 1994, 39, 2, 649.
    Reference 2:
        bhakuni, r.s.; jain, d.c.; sharma, r.p.; an improved procedure for the synthesis of ethers of dihydroartemisinin. indian j chem 1995, 34b, 6, 529.
    Reference 3:
        el-feraly, f.s.; al-yahya, m.a.; orabi, k.y.; mcphail, d.r.; mcphail, a.t.; a new method for the preparation of arteether and its c-9 epimer. j nat prod 1992, 55, 7, 878.
    Reference 4:
        pu, y.-m.; ziffer, h.; synthesis of 11-[3h]-arteether, an experimental antimalarial drug. j label compd radiopharm 1993, 33, 11, 1013.
    Reference 5:
        singh, c.; tiwari, p.; a one-pot conversion of artemisinin to its ether derivatives. tetrahedron lett 2002, 43, 40, 7235.
    Reference 6:
        lin, a.j.; klayman, d.l.; milhous, w.k. (department of the army); novel antimalarial dihydroartemisinin derivs.. us 4791135 .
    Reference 7:
        brossi, a.; venugopalan, b.; gerpe, l.g.; yeh, h.j.c.; flippen-anderson, j.l.; buchs, p.; luo, x.d.; milhous, w.; peters, w.; arteether, a new antimalarial drug: synthesis and antimalarial properties. j med chem 1988, 31, 3, 645.
    Reference 8:
        kumar, s.; jain, d.c.; bhakuni, r.s.; saxena, s.; vishwakarma, r.a. (council of scientific and industrial research); preparation of arteethers. gb 2360517 .
    Reference 9:
        kumar, s.; jain, d.c.; bhakuni, r.s.; saxena, s.; vishwakarma, r.a. (council of scientific and industrial research); process for the preparation of arteethers from dihydroartemisinin. us 6346631 .

    Route 2
    condensation of dihydroartemisinin (i) with ethyl glycolate in the presence of bf3?et2o in anhydrous diethyl ether produces a mixture of the desired glycolate adduct (ii) along with the title ethoxy derivative as a byproduct (5).
    List of intermediates No.
    (e)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal (i)
    Reference 1:
        lin, a.j.; klayman, d.l.; milhous, w.k. (department of the army); novel antimalarial dihydroartemisinin derivs.. us 4791135 .

    Route 3
    the synthesis of a deuterated analogue of artemether starting from the previously reported carboxylic acid (i) is shown in scheme 14079601c. alkylation of the dilithium derivative of (i) with cd3i gives the alpha-methyl acid (ii) as a single stereoisomer. ozonolysis of (ii), followed by acid-catalyzed cyclization affords the deuterated artemisinin (iii). reduction of lactone (iii) by means of dibal provides lactol (iv). finally, the target ethyl ether is formed by treatment of (iv) with ethanol and boron trifluoride etherate (10).
    List of intermediates No.
    2-(4-methoxyphenyl)acetic acid; p-methoxyphenyl formate; homoanisic acid; p-methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid (iii)
    (e)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal (iv)
    Reference 1:
        avery, m.a.; et al.; deuterated antimalarials: synthesis of trideutero-artemisinin, dihydroartemisinin, and arteether. j label compd radiopharm 1996, 38, 3, 249.

    中国竞彩网专家推荐 www.betsyco.net 来源:药化网

    作者:药化小编

    摘要:本文合成路线介绍的是药物中文名蒿乙醚;英文名beta-Arteether;Artemotil;Arteether;SM-227;E MAL;Artecef;CAS[75887-54-6]

     
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