药物详细合成路线
| Name | TOP-53 | | Chemical Name | [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 | | CAS | 147238-98-0 | | Related CAS | 148262-19-5 (free base) | | Formula | C28H38Cl2N2O7 | | Structure |  | | Formula Weight | 585.53026 | | Stage | I 期临床 | | Company | Taiho (Originator) | | Activity/Mechanism | ONCOLYTIC DRUGS, DNA Topoisomerase II Inhibitors, Epipodophyllotoxins | | Syn. Route | 1 | | Route 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. | | |  | | List of intermediates | No. | | 2-[(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)methyl]-n,n-diethyl-1-phenylcyclopropanecarboxamide | (i) | | 2-[(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)methyl]-1-phenylcyclopropanecarboxylic acid | (ii) | | 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid | (iii) | | 4-amino-5-chloro-2-methoxybenzoyl chloride | (iv) | | 5-(2-hydroxyethoxy)-2-(3-hydroxy-4-methoxyphenyl)-7-[[(2s,3r,4s,5s)-3,4,5-trihydroxy-6-([[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]methyl)tetrahydro-2h-pyran-2-yl]oxy]-4h-chromen-4-one | (v) | | 5-(2-hydroxyethoxy)-2-[3-(2-hydroxyethoxy)-4-methoxyphenyl]-7-[[(2s,3r,4s,5s)-3,4,5-trihydroxy-6-([[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]methyl)tetrahydro-2h-pyran-2-yl]oxy]-4h-chromen-4-one | (vi) | | | Reference 1: leeson, p.a.; castaner, j.; top-53. drugs fut 1996, 21, 11, 1136. Reference 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 . Reference 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. |
|
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TOP-53 二盐酸盐；英文名TOP-53；CAS[147238-98-0]
|
