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【结 构 式】 
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【药物名称】Etoposide, VP-16, VP-16-213, NSC-141540, EPEG, Etopophos, Lastet, Etosid, Vepeside, Etopol, Vepesid 【化学名称】4'-Demethylepipodophyllotoxin 4-(4,6-O-ethylidene-beta-D-glucopyranoside) 【CA登记号】33419-42-0 【 分 子 式 】C29H32O13 【 分 子 量 】588.57059 |
【开发单位】Novartis (Originator), Nippon Kayaku (Not Determined), Amgen (Licensee), Bristol-Myers Squibb (Licensee), Sparta (Licensee), Wyeth Pharmaceuticals (Licensee) 【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, DNA Topoisomerase II Inhibitors, Epipodophyllotoxins |
合成路线1
By reaction of 4,6-O-ethylidene-2,3-di-O-acetyl-beta-D-glucopyranose (I) and 4'-benzyloxycarbonyl-4'-demethyl-epipodophyllotoxin (II) in the presence of boron trifluoride etherate to give the compound (III), which is treated with Zn(OAc)2 and NaOAc followed by reduction with Pd-C.
| 【1】 Kuhn, M.; et al.; Verhafren zur Herstellung von Glucosiden. AT 303270B; AT 319971B; CH 514578; NL 6901619 . |
| 【2】 Cabanillas, F.; Etoposide. Drugs Fut 1979, 4, 4, 257. |
| 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) | 33218 | (2R,4aR,6R,7R,8S,8aR)-7-(acetoxy)-6-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C12H18O8 | 详情 | 详情 | |
| (II) | 15774 | 4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl benzyl carbonate | C29H26O10 | 详情 | 详情 | |
| (III) | 33219 | (2R,4aR,6R,7R,8S,8aR)-6-[[(5S,5aR,8aR,9R)-9-(4-[[(benzyloxy)carbonyl]oxy]-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]oxy]-7-(acetoxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C41H42O17 | 详情 | 详情 |
合成路线2
The condensation of dibenzyl-sugar (II) with 4'-demethyl-epipodophyllotoxin (I) by means of BF3·Et2O in acetonitrile gives a mixture of the alpha and beta coupled products (IV) + (III), which by crystallization in dichloromethane/methanol afforded pure diastereomer beta (III). Finally this compound is debenzylated by hydrogenolysis with H2 over Pd/C in THF.
| 【1】 Silverberg, L.J.; et al.; A crystallization-induced steroselective glycosidation reaction in the synthesis of the anticancer drug etoposide. Org Lett 2000, 2, 21, 3281. |
| 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) | 13053 | (5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | 6559-91-7 | C21H20O8 | 详情 | 详情 |
| (II) | 13055 | (2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol | C22H26O6 | 详情 | 详情 | |
| (III) | 41886 | (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C43H44O13 | 详情 | 详情 | |
| (IV) | 41891 | (5R,5aR,8aR,9S)-9-[[(2R,4aR,6S,7R,8R,8aS)-7,8-bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C43H44O13 | 详情 | 详情 |