|
【结 构 式】 
|
【药物名称】TOP-53 【化学名称】[5R-(5alpha,5abeta,8aalpha,9beta)]-9-[2-[N-[2-(Dimethylamino)ethyl]-N-methylamino]ethyl]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6-one dihydrochloride 【CA登记号】147238-98-0, 148262-19-5 (free base) 【 分 子 式 】C28H38Cl2N2O7 【 分 子 量 】585.53026 |
【开发单位】Taiho (Originator) 【药理作用】ONCOLYTIC DRUGS, DNA Topoisomerase II Inhibitors, Epipodophyllotoxins |
合成路线1
The condensation of 4'-O-(benzyloxycarbonyl)-4'-demethylepipodophyllotoxin (I) with allyltrimethylsilane (II) by means of boron trifluoride ethearate in dichloromethane gives 4beta-allyl-4'-O-(benzyloxycarbonyl)-4'-demethyl-4-desoxypodophyllotoxin (III), which is oxidized with OsO4 and N-methylmorpholine (NMO) in acetone to the substituted acetaldehyde (IV). The reductocondensation of (IV) with N,N,N'-trimethylethylenediamine (V) by means of sodium cyanoborohydride and acetic acid in CHCl3 affords the protected final product (VI), which is finally hydrogenated with H2 over Pd/C in methanol.
| 【1】 Leeson, P.A.; Castaner, J.; TOP-53. Drugs Fut 1996, 21, 11, 1136. |
| 【2】 Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.; Takeda, S.; Kobunai, T.; Yamaguchi, H.; Wierzba, K. (Taiho Pharmaceutical Co., Ltd.); 4-Desoxy-4-epipodophyllotoxin deriv. or pharmaceutically aceptable salt thereof. EP 0522173; JP 1993503298; WO 9212982 . |
| 【3】 Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.; Wierzba, K.; Shibata, J.; Sugimoto, Y.; Yamada, Y.; Antitumor agents. 3. Synthesis and biological activity of 4beta-alkyl derivatives containing hydroxy, amino, and amido groups of 4'-O-demethyl-4-desoxypodophyllotoxin as antitumor agents. J Med Chem 1993, 36, 12, 1689-99. |
| 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) | 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 | |
| (II) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (III) | 15776 | 4-[(5R,5aR,8aR,9S)-9-allyl-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 | C32H30O9 | 详情 | 详情 | |
| (IV) | 15777 | 4-[(5R,5aR,8aR,9S)-6-oxo-9-(2-oxoethyl)-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 | C31H28O10 | 详情 | 详情 | |
| (V) | 15778 | N-[2-(dimethylamino)ethyl]-N-methylamine; N,N,N'-trimethyl-1,2-ethanediamine; N(1),N(1),N(2)-trimethyl-1,2-ethanediamine | 142-25-6 | C5H14N2 | 详情 | 详情 |
| (VI) | 15779 | 4-((5R,5aR,8aR,9S)-9-[2-[[2-(dimethylamino)ethyl](methyl)amino]ethyl]-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 | C36H42N2O9 | 详情 | 详情 |