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【结 构 式】 
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【分子编号】22370 【品名】Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol 【CA登记号】 |
【 分 子 式 】C15H24O5 【 分 子 量 】284.35256 【元素组成】C 63.36% H 8.51% O 28.13% |
合成路线1
该中间体在本合成路线中的序号：(II)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).
| 【1】 Pu, Y.M.; Ziffer, H.; Diastereofacial additions to a beta-substituted glycal, anhydrodihydroartemisinin. Heterocycles 1994, 39, 2, 649. |
| 【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. |
| 【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. |
| 【4】 Pu, Y.-M.; Ziffer, H.; Synthesis of 11-[3H]-arteether, an experimental antimalarial drug. J Label Compd Radiopharm 1993, 33, 11, 1013. |
| 【5】 Singh, C.; Tiwari, P.; A one-pot conversion of artemisinin to its ether derivatives. Tetrahedron Lett 2002, 43, 40, 7235. |
| 【6】 Lin, A.J.; Klayman, D.L.; Milhous, W.K. (Department of the Army); Novel antimalarial dihydroartemisinin derivs.. US 4791135 . |
| 【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. |
| 【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 . |
| 【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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 63568 | 1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-9-ene | C15H22O4 | 详情 | 详情 | |
| (IV) | 63569 | (1R,4S,5R,8S,9S,10S,12R,13R)-10-ethoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecane | C17H28O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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).
| 【1】 Lin, A.J.; Klayman, D.L.; Milhous, W.K. (Department of the Army); Novel antimalarial dihydroartemisinin derivs.. US 4791135 . |
合成路线3
该中间体在本合成路线中的序号：(IV)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).
| 【1】 Avery, M.A.; et al.; Deuterated antimalarials: Synthesis of trideutero-artemisinin, dihydroartemisinin, and arteether. J Label Compd Radiopharm 1996, 38, 3, 249. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63571 | C20H34O4 | 详情 | 详情 | ||
| (II) | 63572 | C21H36O4 | 详情 | 详情 | ||
| (III) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (IV) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Artemisinin (I) was reduced to the dihydro analogue (II), and subsequently the 10-hydroxyl group was substituted for a fluorine atom using diethylaminosulfur trifluoride. The desired 10-beta-isomer (III) was then separated by column chromatography. Finally, boron trifluoride-promoted Friedel Crafts condensation with furan (IV) at low temperature provided the target furyl compound, the major 10-beta isomer being isolated by chromatography on Florisil.
| 【1】 Posner, G.H.; Parker, M.H.; Northrop, J.; Elias, J.S.; Ploypradith, P.; Xie, S.; Shapiro, T.A.; Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family. J Med Chem 1999, 42, 2, 300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 22371 | (1R,4S,5R,8S,9R,10R,12S,13R)-10-fluoro-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane | C15H23FO4 | 详情 | 详情 | |
| (IV) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Coupling of dihydroartemisinin (I) with allyl trimethylsilane in the presence of boron trifluoride etherate gave the 10beta-allyl deoxo derivative (II). Subsequent ozonization of the allyl double bond of (II), followed by reductive treatment with NaBH4, provided alcohol (III). Finally, alkylation of (III) with 2-fluorobenzyl bromide (IV) in the presence of NaH furnished the corresponding 2-fluorobenzyl ether.
| 【1】 Searle, N.L.; Maggs, J.L.; Kan, K.-W.; Ward, S.A.; O'Neill, P.M.; Raynes, K.; Park, K.; Storr, R.C.; Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether. J Med Chem 1999, 42, 26, 5487. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 | |
| (I) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (II) | 38773 | (1R,4S,5R,8S,9R,10R,12R,13R)-10-allyl-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane | C18H28O4 | 详情 | 详情 | |
| (III) | 38774 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadec-10-yl]-1-ethanol | C17H28O5 | 详情 | 详情 | |
| (IV) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Dihydroartemisinin (II) was prepared by NaBH4 reduction of artemisinin (I). Condensation of (II) with 2-bromoethanol (A) in the presence of boron trifluoride etherate yielded the 10beta-bromoethyl acetal (III). Finally, reaction of (III) with dimethylamine in DMF provided the desired amine, which was finally converted to the oxalate salt.
| 【1】 Pan, J.-P.; Jiang, H.-J.; Wu, J.-M.; Zhu, Y.-M.; Wu, G.-S.; Li, Y.; Synthesis and antimalarial activity of artemisinin derivatives containing an amino group. J Med Chem 2000, 43, 9, 1635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 40705 | (1R,4S,5R,8S,9R,10S,12R,13R)-10-(2-bromoethoxy)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane; 2-bromoethyl (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadec-10-yl ether | C17H27BrO5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Coupling of dihydroartemisinin (I) with p-trifluoromethylphenol (II) in the presence of trimethylsilyl triflate and silver perchlorate at -78 C produced the corresponding aryl ether as an epimeric mixture. The major 10-beta isomer was then isolated from the reaction mixture by column chromatography.
| 【1】 O'Neill, P.M.; et al.; Application of the TMSOTf-AgClO4 activator system to the synthesis of novel, potent, C-10 phenoxy derivatives of dihydroartemisinin. Tetrahedron Lett 1999, 40, 51, 9129. |
| 【2】 O'Neill, P.M.; Miller, A.; Bishop, L.P.D.; et al.; Synthesis, antimalarial activity, biomimetic iron(I) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin. J Med Chem 2001, 44, 1, 58. |
| 【3】 Ward, S.A.; O'Neill, P.M. (Ultrafine Ltd.); Peroxide-based antimalarial cpds.. WO 0104123 . |
合成路线8
该中间体在本合成路线中的序号：(II)Reduction of artemisinin (I) with NaBH4 at low temperature provided dihydroartemisinin (II), which was subsequently converted to the alpha-acetate (III) upon treatment with acetyl chloride in pyridine. The bis(trimethylsilyl) enol ether (V) - prepared by silylation of 1,4-diacetylbenzene (IV) with trimethylsilyl triflate - was then coupled to dihydroartemisinin acetate (III) in the presence of SnCl4 at -78 C to produce a diastereoisomeric mixture of adducts (VIa-c). The title alpha,alpha-dimer was then isolated as a minor component by means of preparative HPLC.
| 【1】 Borstnik, K.; Posner, G.H.; Paik, I.-H.; Dolan, P.; Kensler, T.W.; Xie, S.; Shapiro, T.A.; Northrop, J.; New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorg Med Chem 2002, 10, 1, 227. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 56088 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]-1-(4-{2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]acetyl}phenyl)-1-ethanone | C40H54O10 | 详情 | 详情 | |
| (VIb) | 56089 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]-1-(4-{2-[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]acetyl}phenyl)-1-ethanone | C40H54O10 | 详情 | 详情 | |
| (VIc) | 56090 | 2-[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]-1-(4-{2-[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]acetyl}phenyl)-1-ethanone | C40H54O10 | 详情 | 详情 | |
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 56087 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl acetate | C17H26O6 | 详情 | 详情 | |
| (IV) | 42273 | 1-(4-acetylphenyl)-1-ethanone | 1009-61-6 | C10H10O2 | 详情 | 详情 |
| (V) | 42274 | trimethylsilyl 1-(4-[1-[(trimethylsilyl)oxy]vinyl]phenyl)vinyl ether; trimethyl[[1-(4-[1-[(trimethylsilyl)oxy]vinyl]phenyl)vinyl]oxy]silane | C16H26O2Si2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Reduction of artemisinin (I) with DIBAL, followed by acetylation of the resultant lactol (II) with Ac2O/DMAP leads to dihydroartemisinin acetate (III). Treatment of the allylic dichloride (IV) with trimethylsilyllithium provides the bis-silane derivative (V). Then, coupling of dihydroartemisinin acetate (III) with bis-silane (V) in the presence of SnCl4 gives rise to the artemisinin dimer (VI).
| 【1】 Posner, G.H.; Paik, I.-P.; Sur, S.; McRiner, A.J.; Borstnik, K.; Zie, S.; Shapiro, T.A.; Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem 2003, 46, 6, 1060. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 56087 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl acetate | C17H26O6 | 详情 | 详情 | |
| (IV) | 64026 | 3-chloro-2-(chloromethyl)-1-propene | C4H6Cl2 | 详情 | 详情 | |
| (V) | 64027 | trimethyl{2-[(trimethylsilyl)methyl]-2-propenyl}silane | C10H24Si2 | 详情 | 详情 | |
| (VI) | 64028 | (1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-10-(2-{[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]methyl}-2-propenyl)-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecane | C34H52O8 | 详情 | 详情 |