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【结 构 式】 
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【药物名称】Rishirilide B 【化学名称】(+)-(1R*,2R*,3R*)-1,2,8-Trihydroxy-3-methyl-1-(3-methylbutyl)-4-oxo-1,2,3,4-tetrahydroanthracene-2-carboxylic acid 【CA登记号】93361-67-2 【 分 子 式 】C21H24O6 【 分 子 量 】372.42183 |
【开发单位】Otsuka (Originator) 【药理作用】Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombolytics |
合成路线1
The cyclization of acetoacetic ester (I) with crotonaldehyde (II) by means of Na and 2-(trimethylsilyl)ethanol (A) in ethyl ether gives the cyclohexenone carboxylic ester (III), which is hydroxylated by means of NaH, Tbdms-OTf and dimethyldioxirane (DMDO) in DMF, yielding the alpha-hydroxy compound (IV). The bromination of (IV) with NBS and AIBN, followed by treatment with Ag2CO3 in acetone/water, affords the diol (V), which is oxidized with DMP to the cyclohexenedione (VI). The cyclization of (VI) with benzocyclobutane (VII) in hot toluene provides the tricyclic dione (VIII), which is aromatized by means of CSA in pyridine/MeOH, furnishing the dihydroanthraquinone (IX). The Grignard condensation of (IX) with isoamylmagnesium bromide (X) in THF gives the adduct (XI), which is finally desilylated by means of TAS-F in THF.
| 【1】 Danishefsky, S.J.; Allen, J.G.; The total synthesis of (±)-rishirilide B. J Am Chem Soc 2001, 123, 2, 351. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (I) | 45600 | 2-(trimethylsilyl)ethyl 3-oxobutanoate | C9H18O3Si | 详情 | 详情 | |
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (III) | 45601 | 2-(trimethylsilyl)ethyl 6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 367-57-7 | C13H22O3Si | 详情 | 详情 |
| (IV) | 45602 | 2-(trimethylsilyl)ethyl (1R,6S)-1-hydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O4Si | 详情 | 详情 | |
| (V) | 45603 | 2-(trimethylsilyl)ethyl (1R,6S)-1,5-dihydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O5Si | 详情 | 详情 | |
| (VI) | 45604 | 2-(trimethylsilyl)ethyl (1R,6R)-1-hydroxy-6-methyl-2,5-dioxo-3-cyclohexene-1-carboxylate | C13H20O5Si | 详情 | 详情 | |
| (VII) | 45605 | (7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl tert-butyl(dimethyl)silyl ether; [((7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl)oxy](tert-butyl)dimethylsilane | C26H50O3Si3 | 详情 | 详情 | |
| (VIII) | 45606 | 2-(trimethylsilyl)ethyl (2R,3R,4aS,9R,9aR,10S)-8,9,10-tris[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4,4a,9,9a,10-octahydro-2-anthracenecarboxylate | C39H70O8Si4 | 详情 | 详情 | |
| (IX) | 45607 | 2-(trimethylsilyl)ethyl (2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C27H38O6Si2 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 45608 | 2-(trimethylsilyl)ethyl (1R,2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-1,2-dihydroxy-1-isopentyl-3-methyl-4-oxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C32H50O6Si2 | 详情 | 详情 |