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【结 构 式】 
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【分子编号】35102 【品名】(3-bromo-1-propynyl)(tert-butyl)dimethylsilane 【CA登记号】 |
【 分 子 式 】C9H17BrSi 【 分 子 量 】233.22348 【元素组成】C 46.35% H 7.35% Br 34.26% Si 12.04% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of the propargyl tetrahydropyranyl ether (I) with TBDMS-Cl and BuLi in THF gives the silylated acetylene (II), which is treated with Br2 and PPh3 to yield the silylated propargyl bromide (III). The reaction of (III) with the pyranopyridone (IV) by means of NaH and LiBr in DMF/DME affords the alkylated pyranopyridone (V), which is cyclized with 4-acetoxyphenyl isocyanide (VI) by means of hexamethyldistannane in refluxing benzene to provide the silylated acetoxycamptothecin (VII). Finally, this compound is deacetylated with K2CO3 in methanol.
| 【1】 Bom, D.; et al.; The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 2000, 43, 21, 3970. |
| 【2】 Bom, D.; Curran, D.P.; Josien, H. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. EP 1017399; JP 2001513567; US 6150343; WO 9909996 . |
| 【3】 Bom, D.; Curran, D.P.; Josien, H.; Burke, T.G. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0035924 . |
| 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) | 43853 | (1S,5S,7R,10S,12S,16S)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6(11),14-diene-7,10,12-triol | C32H58O6Si2 | 详情 | 详情 | |
| (II) | 49254 | 4,5-dichloro-2-iodoaniline; tert-butyl(dimethyl)[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]silane | C14H26O2Si | 详情 | 详情 | |
| (III) | 35102 | (3-bromo-1-propynyl)(tert-butyl)dimethylsilane | C9H17BrSi | 详情 | 详情 | |
| (IV) | 49255 | (4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C10H10INO4 | 详情 | 详情 | |
| (V) | 49256 | (4S)-7-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C19H26INO4Si | 详情 | 详情 | |
| (VI) | 49257 | C9H7NO2 | 详情 | 详情 | ||
| (VII) | 49258 | (4S)-11-[tert-butyl(dimethyl)silyl]-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl acetate | C28H32N2O6Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)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-(tert-butyldimethylsilyl)propargyl bromide (VII), yielding (VIII). Finally, radical annulation of (VIII) with phenyl isonitrile (IX) in the presence hexamethylditin furnished the title pentacyclic 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. |
| 【2】 Burke, T.G.; Curran, D.P.; Bom, D. (University of Kentucky; University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0061146 . |
| 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) | 35102 | (3-bromo-1-propynyl)(tert-butyl)dimethylsilane | C9H17BrSi | 详情 | 详情 | |
| (VIII) | 35103 | 8-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C20H28INO4Si | 详情 | 详情 | |
| (IX) | 35104 | Benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |