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【结 构 式】 
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【药物名称】Afeletecan hydrochloride, BAY-38-3441 【化学名称】N-[4-(6-Deoxy-3-O-methyl-beta-L-galactopyranosyloxy)phenylaminothiocarbonyl]-L-histidyl-L-valine 4(S)-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl ester hydrochloride 【CA登记号】215604-74-3, 215604-66-3 (diastereomeric mixture), 215604-75-4 (free base) 【 分 子 式 】C45H50ClN7O11S 【 分 子 量 】932.45755 |
【开发单位】Bayer (Originator) 【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Camptothecins, DNA-Intercalating Drugs |
合成路线1
Acylation of the tertiary 20-hydroxy group of camptothecin (I) with N-Boc-valine-N-carboxyanhydride (II) afforded the corresponding ester (III). Subsequent acidic N-Boc group cleavage gave amino ester (IV). This was coupled with N-Boc-histidine (V) to furnish, after treatment with trifluoroacetic acid, the histidyl-valyl camptothecin ester (VI).
| 【1】 Lerchen, H.-G.; et al.; Design and optimization of 20-O-linked camptothecin glyconjugates as anticancer agents. J Med Chem 2001, 44, 24, 4186. |
| 【2】 Baumgarten, J.; Von dem Bruch, K.; Lerchen, H.-G.; Sperzel, M. (Bayer AG); 20(S) Camptothecin glycoconjugates. DE 19801037; DE 19813137; EP 0981542; JP 2001526661; WO 9851703 . |
| 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) | 25916 | (4S)-4-hydroxy-4-methyl-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H16N2O4 | 详情 | 详情 | |
| (II) | 35318 | tert-butyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate | 141468-55-5 | C11H17NO5 | 详情 | 详情 |
| (III) | 52487 | 4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-methylbutanoate | C30H33N3O7 | 详情 | 详情 | |
| (IV) | 52488 | 4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-amino-3-methylbutanoate | C25H25N3O5 | 详情 | 详情 | |
| (V) | 42808 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-5-yl)propionic acid | 17791-52-5 | C11H17N3O4 | 详情 | 详情 |
| (VI) | 52489 | 4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-{[2-amino-3-(1H-imidazol-5-yl)propanoyl]amino}-3-methylbutanoate | C31H32N6O6 | 详情 | 详情 |
合成路线2
Regioselective O-methylation of p-nitrophenyl-beta-L-fucopyranoside (VII) by means of dibutyltin oxide and iodomethane provided the 3-O-methyl pyranoside (VIII). Subsequent catalytic hydrogenation of the nitro group of (VIII) over PtO2 gave aniline (IX), which was further converted to the isothiocyanate (X) upon treatment with thiophosgene and ethyl diisopropylamine. Finally, coupling between isothiocyanate (X) and amine (VI) furnished the target thiourea adduct, which was finally isolated as the corresponding hydrochloride salt.
| 【1】 Lerchen, H.-G.; et al.; Design and optimization of 20-O-linked camptothecin glyconjugates as anticancer agents. J Med Chem 2001, 44, 24, 4186. |
| 【2】 Baumgarten, J.; Von dem Bruch, K.; Lerchen, H.-G.; Sperzel, M. (Bayer AG); 20(S) Camptothecin glycoconjugates. DE 19801037; DE 19813137; EP 0981542; JP 2001526661; WO 9851703 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52489 | 4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-{[2-amino-3-(1H-imidazol-5-yl)propanoyl]amino}-3-methylbutanoate | C31H32N6O6 | 详情 | 详情 | |
| (VII) | 52490 | 2-methyl-6-[(4-nitrophenyl)oxy]tetrahydro-2H-pyran-3,4,5-triol | C12H15NO7 | 详情 | 详情 | |
| (VIII) | 52491 | 2-methyl-4-(methyloxy)-6-[(4-nitrophenyl)oxy]tetrahydro-2H-pyran-3,5-diol | C13H17NO7 | 详情 | 详情 | |
| (IX) | 52492 | 2-[(4-aminophenyl)oxy]-6-methyl-4-(methyloxy)tetrahydro-2H-pyran-3,5-diol | C13H19NO5 | 详情 | 详情 | |
| (X) | 52493 | 2-[(4-isothiocyanatophenyl)oxy]-6-methyl-4-(methyloxy)tetrahydro-2H-pyran-3,5-diol | C14H17NO5S | 详情 | 详情 |