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【结 构 式】 
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【药物名称】DB-38 【化学名称】 【CA登记号】 【 分 子 式 】C24H27N3O4Si 【 分 子 量 】449.58649 |
【开发单位】University of Kentucky (Originator), Tigen Pharmaceuticals (Codevelopment) 【药理作用】ONCOLYTIC DRUGS, Camptothecins, DNA Topoisomerase I Inhibitors |
合成路线1
The known enol ether (I) was dihydroxylated with OsO4 and then oxidatively cleaved to the keto formate (II) by means of Pb(OAc)4. Reformatskii reaction of (II) with (tert-butoxycarbonyl)methylzinc bromide gave hydroxyester (III). Further cyclization of (III) using trifluroacetic acid produced lactone (IV). Halogenation with iodine monochloride afforded iodopyridine (V). Then, cleavage of the methyl ether of (V) employing trimethylsilyl iodide generated the pyridone lactone (VI), which was N-alkylated with 3-(trimethylsilyl)propargyl bromide (VII), yielding (VIII). Radical annulation of (VIII) with isonitrile (IX) in the presence hexamethylditin furnished the pentacyclic system (X). Finally, removal of the N-Boc protecting group of (X) yielded the title compound.
| 【1】 Bom, D.; et al.; Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 1999, 42, 16, 3018. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | ||
| (I) | 35096 | 4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine | C14H21NO2Si | 详情 | 详情 | |
| (II) | 35097 | [2-methoxy-4-propionyl-6-(trimethylsilyl)-3-pyridinyl]methyl formate | C14H21NO4Si | 详情 | 详情 | |
| (III) | 35098 | tert-butyl 3-[3-[(formyloxy)methyl]-2-methoxy-6-(trimethylsilyl)-4-pyridinyl]-3-hydroxypentanoate | C20H33NO6Si | 详情 | 详情 | |
| (IV) | 35099 | 5-ethyl-5-hydroxy-9-methoxy-7-(trimethylsilyl)-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C15H23NO4Si | 详情 | 详情 | |
| (V) | 35100 | 5-ethyl-5-hydroxy-7-iodo-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H14INO4 | 详情 | 详情 | |
| (VI) | 35101 | 5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H12INO4 | 详情 | 详情 | |
| (VII) | 35105 | (3-bromo-1-propynyl)(trimethyl)silane | 38002-45-8 | C6H11BrSi | 详情 | 详情 |
| (VIII) | 35106 | 5-ethyl-5-hydroxy-7-iodo-8-[3-(trimethylsilyl)-2-propynyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C17H22INO4Si | 详情 | 详情 | |
| (IX) | 35107 | Carbamic acid, (4-cyanophenyl)-, 1,1-dimethylethyl ester (9CI); tert-butyl 4-cyanophenylcarbamate | 143090-18-0 | C12H14N2O2 | 详情 | 详情 |
| (X) | 35108 | tert-butyl 5-ethyl-5-hydroxy-3,15-dioxo-12-(trimethylsilyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinolin-10-ylcarbamate | C29H35N3O6Si | 详情 | 详情 |