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【结 构 式】

【药物名称】Artemisininelactol methyl ether, Artemether, SM-224, Artemos, Artenam, Artemetheri, Paluther

【化学名称】(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine

【CA登记号】71963-77-4

【 分 子 式 】C16H26O5

【 分 子 量 】298.38262

【开发单位】Academy of Military Medical Sciences (Originator), Kunming Pharmaceutical (Originator), Shanghai Institute Materia Medica (Originator), Arenco (Not Determined), Aventis Pharma (Licensee)

【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7

合成路线1

Reduction of qinghaosu (artemisine) (I) by means of sodium borohydride gives a hemiacetal, artemisininelactol (II). Interaction of the latter compound with methanol in the presence of boron triftuoride gives artemether. It can be prepared even more easily by treating artemisininelactol with methanol in acidic medium. The epimers can be separated by chromatography. However, the product without separation of epimers has been used for clinical studies.

参考文献 中间体
【1】 The chemistry and synthesis of qinghaosu derivatives. J Tradit Chin Med 1982, 2, 1, 9-16.
【2】 Singh, C.; Tiwari, P.; A one-pot conversion of artemisinin to its ether derivatives. Tetrahedron Lett 2002, 43, 40, 7235.
【3】 Ru-yun, J.; Artemether. Drugs Fut 1982, 7, 10, 716.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIa) 31980 (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)]hexadecan-10-ol C15H24O5 详情 详情
(IIb) 31981 (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)]hexadecan-10-ol C15H24O5 详情 详情
(IIIa) 31982 methyl (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 ether; (1R,4S,5R,8S,9R,10R,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane C16H26O5 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

合成路线2

　

参考文献 中间体
【1】 Deshpande VH, Bhonsle JB, Pandey B, et al. 1994. New synthesis strategies towards(+) -artemisinin. Tetrahedron Lett, 35(30):5489～5492.
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) 10208 L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone 14073-97-3 C10H18O 详情 详情
(II) 10209 (3R,6S)-2-[(Dimethylamino)methyl]-6-isopropyl-3-methylcyclohexanone C13H25NO 详情 详情
(III) 10210 (4aS,5R,8S)-8-Isopropyl-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O 详情 详情
(IV) 10211 (1aS,4aS,5R,8S,8aS)-8-Isopropyl-5-methylhexahydro-1aH-naphtho[1,8a-b]oxiren-2(3H)-one C14H22O2 详情 详情
(V) 10212 (2S,4aS,5R,8S)-8-Isopropyl-5-methyloctahydro-2,8a(1H)-naphthalenediol C14H26O2 详情 详情
(VI) 10213 (2S,4aS,5R,8S,8aS)-8a-Hydroxy-8-isopropyl-5-methyldecahydro-2-naphthalenyl acetate C16H28O3 详情 详情
(VII) 67030 (3aS,6R,6aS,9S,10aR)-3,6-Dimethyldecahydro-2H-naphtho[8a,1-b]furan-9-ol 　 C14H24O2 详情 详情
(VIII) 10215 (3aS,6R,6aS,10aR)-3,6-Dimethyloctahydro-2H-naphtho[8a,1-b]furan-9(10H)-one C14H22O2 详情 详情
(IX) 10216 (4aS,5R,8S)-8-(2-Hydroxy-1-methylethyl)-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O2 详情 详情
(X) 10217 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-5-methyloctahydro-2(1H)-naphthalenone C14H24O2 详情 详情
(XI) 10218 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-2,5-dimethyldecahydro-2-naphthalenol C15H28O2 详情 详情
(XII) 10219 2-[(1R,4R,4aS,8aS)-7-hydroxy-4,7-dimethyldecahydro-1-naphthalenyl]propyl acetate C17H30O3 详情 详情
(XIII) 10220 2-[(1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]propyl acetate C17H28O2 详情 详情
(XIV) 10221 2-[(1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]-1-propanol C15H26O 详情 详情
(XV) 67031 3-((4S,4aR,7S,8R)-4,7-dimethyl-4,4a,5,6,7,8-hexahydro-3H-isochromen-8-yl)propanoic acid 　 C14H22O3 详情 详情
(XVI) 10224 (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)]hexadecane C15H24O4 详情 详情

合成路线3

　

参考文献 中间体
【1】 Deshpande VH, Bhonsle JB, Pandey B, et al. 1994. New synthesis strategies towards(+) -artemisinin. Tetrahedron Lett, 35(30):5489～5492.
【2】 Liu HJ, Yeh WL, Chew SY. 1993. Atotal synthesis of antimalarial natural product (+) -quinghaosu. Tetrahedron Lett, 34(28): 4435～4438
【3】 Xu XX, Zhu J, Huang DZ, et al. 1986. Total synthesis of arteannuin and deoxyarteannuin. Tetrahedron, 42(3): 819～828.
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) 10225 (3R)-3,7-Dimethyl-6-octenal; L-Citronellal 5949-05-3 C10H18O 详情 详情
(II) 10226 (1R,2S,5R)-2-(2-Hydroxy-1-methylethyl)-5-methylcyclohexanol C10H20O2 详情 详情
(III) 10227 (1R,2S,5R)-2-[2-(Benzyloxy)-1-methylethyl]-5-methylcyclohexanol C17H26O2 详情 详情
(IV) 10228 (2S,5R)-2-[2-(Benzyloxy)-1-methylethyl]-5-methylcyclohexanone C17H24O2 详情 详情
(V) 10230 (2S,3R,6S)-6-[2-(Benzyloxy)-1-methylethyl]-3-methyl-2-(3-oxobutyl)cyclohexanone C21H30O3 详情 详情
(VI) 10231 (4aS,5R,8S)-8-[2-(Benzyloxy)-1-methylethyl]-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C21H28O2 详情 详情
(VII) 10232 (4aS,5R,8R,8aS)-8-[2-(Benzyloxy)-1-methylethyl]-5-methyloctahydro-2(1H)-naphthalenone C21H30O2 详情 详情
(VIII) 10233 (4aS,5R,8R,8aS)-8-[2-(Benzyloxy)-1-methylethyl]-2,5-dimethyldecahydro-2-naphthalenol C22H34O2 详情 详情
(IX) 10234 2-[(1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]propyl benzyl ether; (1R,4R,4aS,8aS)-1-[2-(Benzyloxy)-1-methylethyl]-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene C22H32O 详情 详情
(X) 10235 methyl 2-[(1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]propanoate C16H26O2 详情 详情
(XI) 10236 methyl 2-[(1R,2S,3S,4R)-2-formyl-4-methyl-3-(3-oxobutyl)cyclohexyl]propanoate C16H26O4 详情 详情
(XII) 10237 methyl 2-[(1R,2S,3S,4R)-2-formyl-4-methyl-3-[2-(2-methyl-1,3-dithian-2-yl)ethyl]cyclohexyl]propanoate C19H32O3S2 详情 详情
(XIII) 10238 methyl 2-[(1S,3S,4R)-2-[(Z)-methoxymethylidene]-4-methyl-3-[2-(2-methyl-1,3-dithian-2-yl)ethyl]cyclohexyl]propanoate C20H34O3S2 详情 详情
(XIV) 10239 methyl 2-[(1S,3S,4R)-2-[(Z)-methoxymethylidene]-4-methyl-3-(3-oxobutyl)cyclohexyl]propanoate C17H28O4 详情 详情
(XV) 10240 methyl 2-[(3R,5aS,6R,9S,9aR)-9a-(dimethoxymethyl)-3-methoxy-3,6-dimethyloctahydro-3H-1,2-benzodioxepin-9-yl]propanoate C19H34O7 详情 详情

合成路线4

　

参考文献 中间体
【1】 Yadav JS, Satheesh BR, Sabitha G. 2003. Stereoselective total synthesis of (+) -artemisinin. Tetrahedron Lett, 44(2): 387～389.
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) 61739 (1R)-(+)-trans-Isolimonene; (+)-p-Mentha-2,8-diene; (1R)-(+)-trans-Isolimonene with G.C. 5113-87-1 C10H16 详情 详情
(II) 61740 (2S)-2-[(1R,4R)-4-methyl-2-cyclohexen-1-yl]-1-propanol C10H18O 详情 详情
(III) 61741 (2S)-2-[(1R,4R)-4-methyl-2-cyclohexen-1-yl]propanoic acid C10H16O2 详情 详情
(IV) 61742 (3aS,6R,7R,7aR)-7-iodo-3,6-dimethylhexahydro-1-benzofuran-2(3H)-one C10H15IO2 详情 详情
(V) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(VI) 61744 (3aS,6R,7aS)-3,6-dimethyl-7-(3-oxobutyl)hexahydro-1-benzofuran-2(3H)-one C14H22O3 详情 详情
(VII) 61746 (3aS,6R,7S,7aS)-3,6-dimethyl-7-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]hexahydro-1-benzofuran-2(3H)-one C16H26O2S2 详情 详情
(VIII) 61748 methyl 2-{(1S,2S,3S,4R)-2-hydroxy-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]cyclohexyl}propanoate C17H30O3S2 详情 详情
(IX) 61749 methyl 2-{(1S,3S,4R)-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]-2-oxocyclohexyl}propanoate C17H28O3S2 详情 详情
(X) 61750 methyl 2-{(1S,3S,4R)-2-[(E)-methoxymethylidene]-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]cyclohexyl}propanoate C19H32O3S2 详情 详情
(XI) 10239 methyl 2-[(1S,3S,4R)-2-[(Z)-methoxymethylidene]-4-methyl-3-(3-oxobutyl)cyclohexyl]propanoate C17H28O4 详情 详情
(XIII) 61743 (3S,3aS,6R,7R,7aR)-7-iodo-3,6-dimethylhexahydro-1-benzofuran-2(3H)-one C10H15IO2 详情 详情
(XIV) 61745 (3aS,6R,7R,7aS)-3,6-dimethyl-7-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]hexahydro-1-benzofuran-2(3H)-one C16H26O2S2 详情 详情

合成路线5

　

参考文献 中间体
【1】 Avery MA, Chong WKM, Jennings-White C. 1992. Stereoselective total synthesis of (+) -artemisinin, the antimalarial constitutent of Artemisia annua L. J Am Chem Soc, 114(3): 974～979.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 67032 (6R)-2,2,6-trimethyl-1-oxaspiro[2.5]octan-4-one 　 C10H16O2 详情 详情
(I) 56751 (5R)-5-methyl-2-(1-methylethylidene)cyclohexanone C10H16O 详情 详情
(III) 67033 (5S)-5-methyl-2-(phenylthio)cyclohexanone 　 C13H16OS 详情 详情
(IV) 67034 (5R)-5-methyl-2-(phenylsulfinyl)cyclohexanone 　 C13H16O2S 详情 详情
(V) 67035 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane 87842-52-2 C9H17BrO2 详情 详情
(VI) 67036 (3R,Z)-3-methyl-6-(phenylsulfinyl)-2-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)cyclohexanone 　 C22H30O4S 详情 详情
(VII) 67037 (R,Z)-3-methyl-2-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)cyclohexanone 　 C16H26O3 详情 详情
(VIII) 67038 (Z)-4-methyl-N'-((R,Z)-3-methyl-2-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)cyclohexylidene)benzenesulfonohydrazide 　 C23H34N2O4S 详情 详情
(IX) 67039 (R,Z)-5-methyl-6-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)cyclohex-1-enecarbaldehyde 　 C17H26O3 详情 详情
(X) 67040 ((R,Z)-5-methyl-6-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)cyclohex-1-en-1-yl)(trimethylsilyl)methyl acetate 　 C22H38O4Si 详情 详情
(XI) 67041 2-((2Z,3Z,4R)-4-methyl-3-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)-2-((trimethylsilyl)methylene)cyclohexyl)acetic acid 　 C22H38O4Si 详情 详情
(XII) 67042 2-((1R,2Z,3Z,4S)-4-methyl-3-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethylidene)-2-((trimethylsilyl)methylene)cyclohexyl)propanoic acid 　 C23H40O4Si 详情 详情

合成路线6

　

参考文献 中间体
【1】 Avery MA, Bonk JD, Bupp J. 1996. Radiolabeled antimalarials: synthesis of C-14-artemisinin. J Label Compd Radiopharm, 38(3): 263～267.
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) 67043 　 　 C22H38O4Si 详情 详情
(II) 67044 　 　 14CC22H40O4Si 详情 详情

合成路线7

　

参考文献 中间体
【1】 Bonk JD, Avery MA, Mchrotra S. 1996. Dcuterated antimalarials: synthesis of trideutero-artemisinin, dihydroartemisinin and arteether. J Label Compd Radiopharm, 38(8): 249～251.
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) 67043 　 　 C22H38O4Si 详情 详情
(II) 67045 　 　 C23H37D3O4Si 详情 详情
Extended Information