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【结 构 式】 
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【药物名称】Annamycin LF(lipid formulation), Annamycin, AR-522 【化学名称】3'-Deamino-4-demethoxy-4'-epi-3'-hydroxy-2'-iododoxorubicin 【CA登记号】92689-49-1 【 分 子 式 】C26H25IO11 【 分 子 量 】640.38695 |
【开发单位】Ohio State University (Originator), Antigenics (Licensee) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Breast Cancer Therapy, DRUG DELIVERY, Leukemia Therapy, Liposomes, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Anthracyclines |
合成路线1
The reaction of racemic 4-demethoxydaunomycinone (I) with Br2 followed by hydrolysis in basic medium gives 4-demethoxyadriamycinone (II), which is treated with tert-butyldimethylsilyl chloride and imidazole in DMF to yield the monoprotected compound (III). The condensation of (III) with 3,4-di-O-acetyl-2,6-dideoxy-2-iodo-alpha-L-mannopyranose (IV) by means of N-iodosuccinimide (NIS), followed by chromatographic separation of the diastereomers affords (7S,9S)-14-O-(tert-butyldimethylsilyl)-4-demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-alpha-L-mannopyranosyl)adriamycinone (V). The hydrolysis of (V) with sodium methoxide in methanol gives the silylated compound (VI), which is finally desilylated with tetrabutylammonium fluoride (TBAF) in dichloromethane/THF/pyridine.
| 【1】 Graul, A.; Prous, J.; Castaner, J.; Annamycin. Drugs Fut 1997, 22, 9, 948. |
| 【2】 Horton, D.; Priebe, W. (Ohio State University); 4-Demethoxy-3'-desamino-2'-haloanthracycline and pharmaceutical compsn. US 4537882 . |
| 【3】 Horton, D.; Priebe, W.; Varela, O.; Synthesis of antitumor-active (7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-alpha-L-mannopyranosyl) adriamycinone: Preparative resolution of a racemic anthracyclinone by alkoxyhalogenation of a glycal. Carbohydr Res 1984, 130, C1-3. |
| 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) | 11052 | (9S)-9-Acetyl-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C20H16O7 | 详情 | 详情 | |
| (II) | 11053 | (9S)-9-Glycoloyl-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C20H16O8 | 详情 | 详情 | |
| (III) | 11054 | (9S)-9-(2-[[tert-Butyl(dimethyl)silyl]oxy]acetyl)-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C26H30O8Si | 详情 | 详情 | |
| (IV) | 11055 | (2S,3S,4R,5R,6R)-3-(acetoxy)-6-hydroxy-5-iodo-2-methyltetrahydro-2H-pyran-4-yl acetate | C10H15IO6 | 详情 | 详情 | |
| (V) | 11056 | (2S,3S,4R,5R,6R)-3-(acetoxy)-6-[[(1S,3S)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]acetyl)-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-5-iodo-2-methyltetrahydro-2H-pyran-4-yl acetate | C36H43IO13Si | 详情 | 详情 | |
| (VI) | 11057 | (7S,9S)-9-(2-[[tert-Butyl(dimethyl)silyl]oxy]acetyl)-7-[[(2R,3R,4R,5R,6S)-4,5-dihydroxy-3-iodo-6-methyltetrahydro-2H-pyran-2-yl]oxy]-6,9,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C32H39IO11Si | 详情 | 详情 |
合成路线2
The Diels-Alder cyclization of butadiene (VII) with 1,4-benzoquinone (VIII) in THF gives the naphthalenetrione (IX), which is acylated with acetic anhydride and TEA to yield the tetralone derivative (X). The Grignard reaction of (X) with vinylmagnesium bromide (XI) and CeCl3, followed by acylation with acetic anhydride, affords the tetraline derivative (XII), which is treated with NaBH4 and oxidized with cerium ammonium nitrate to provide the tetrahydronaphthoquinone (XIII). The cyclization of (XIII) with 4-acetoxy-3,4-dihydro-1H-2-benzopyran-1,3-dione (XIV) by means of NaH in THF gives the intermediate (XV), which rearranges to the tetracyclic dione (XVI). The palladium-catalyzed (PdCl2(MeCN)2) rearrangement of (XVI) in toluene yields the allyl acetate derivative (XVII), which is oxidized with peracetic acid and RuCl3 in water/acetonitrile/dichloromethane to afford the protected intermediate (XVIII). Finally, this compound is deprotected and simultaneously epimerized by a treatment with HCl in refluxing isopropanol/water to provide the desired target intermediate (II).
| 【1】 Hottop, T.; et al.; Synthesis of 4-demethoxyadriamycinone utilizing ruthenium-catalyzed oxidation of allyl acetates. Tetrahedron Lett 2001, 42, 19, 3343. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 50740 | (7S,9S)-9-glycoloyl-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C20H16O8 | 详情 | 详情 | |
| (VII) | 50730 | [[(E)-3-(tert-butoxy)-1-methylene-2-propenyl]oxy](trimethyl)silane; (E)-3-(tert-butoxy)-1-methylene-2-propenyl trimethylsilyl ether | C11H22O2Si | 详情 | 详情 | |
| (VIII) | 12633 | Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione | 106-51-4 | C6H4O2 | 详情 | 详情 |
| (IX) | 50731 | 8-(tert-butoxy)-4a,7,8,8a-tetrahydro-1,4,6(5H)-naphthalenetrione | C14H18O4 | 详情 | 详情 | |
| (X) | 50732 | 4-(acetoxy)-5-(tert-butoxy)-7-oxo-5,6,7,8-tetrahydro-1-naphthalenyl acetate | C18H22O6 | 详情 | 详情 | |
| (XI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XII) | 50733 | (2S,4S)-5,8-bis(acetoxy)-4-(tert-butoxy)-2-vinyl-1,2,3,4-tetrahydro-2-naphthalenyl acetate | C22H28O7 | 详情 | 详情 | |
| (XIII) | 50734 | (2S,4S)-4-(tert-butoxy)-5,8-dioxo-2-vinyl-1,2,3,4,5,8-hexahydro-2-naphthalenyl acetate | C18H22O5 | 详情 | 详情 | |
| (XIV) | 50735 | 1,3-dioxo-3,4-dihydro-1H-isochromen-4-yl acetate | C11H8O5 | 详情 | 详情 | |
| (XV) | 50736 | (2S,4S)-6-(acetoxy)-4-(tert-butoxy)-11-hydroxy-5,12-dioxo-2-vinyl-1,2,3,4,5,12-hexahydro-2-naphthacenyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVI) | 50737 | (2S,4S)-2-(acetoxy)-4-(tert-butoxy)-12-hydroxy-6,11-dioxo-2-vinyl-1,2,3,4,6,11-hexahydro-5-naphthacenyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVII) | 50738 | 2-[5-(acetoxy)-4-(tert-butoxy)-12-hydroxy-6,11-dioxo-3,4,6,11-tetrahydro-2(1H)-naphthacenylidene]ethyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVIII) | 50739 | (2S,4R)-2-[2-(acetoxy)acetyl]-4-(tert-butoxy)-2,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-5-naphthacenyl acetate | C28H28O10 | 详情 | 详情 |