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【结 构 式】 
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【药物名称】Epidoxorubicin, Pidorubicin(former Prop INN), 4'-epi-Doxorubicin, 4'-epi-Adriamycin, Epirubicin hydrochloride, 4'-epi-DX, IMI-28, E-ADM, Ellence, Farmorubicina, Pharmorubicin, Farmorubicin 【化学名称】(1S,3S)-3-Glycoloyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranoside hydrochloride 【CA登记号】56420-45-2 (free base) 【 分 子 式 】C27H30ClNO11 【 分 子 量 】579.99325 |
【开发单位】Pfizer (Originator), Kyowa Hakko (Not Determined), National Cancer Institute (Not Determined) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Breast Cancer Therapy, Head and Neck Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Lymphocytic Leukemia Therapy, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Anthracyclines, Antimitotic Drugs, DNA Topoisomerase II Inhibitors |
合成路线1
| 【1】 Van Der Rijst M, Scheeren JW, et aL.1998. A process for preparing epirubicin or acid addition salts thereof from daunorubicin. EP 848009 |
| 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) | 66341 | (8S,10S)-8-acetyl-10-((4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione hydrochloride | C27H29NO10.HCl | 详情 | 详情 | |
| (II) | 16223 | (8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | 21794-55-8 | C21H18O8 | 详情 | 详情 |
| (III) | 66342 | 4-amino-6-methoxy-2-methyltetrahydro-2H-pyran-3-ol hydrochloride | C7H15NO3.HCl | 详情 | 详情 | |
| (IV) | 66346 | 2-oxo-2-(2,4,5,12-tetrahydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)ethyl acetate | C23H20O10 | 详情 | 详情 | |
| (V) | 30693 | 2,2,2-trifluoro-N-[(2S,3S,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H14F3NO4 | 详情 | 详情 | |
| (VI) | 30694 | 2,2,2-trifluoro-N-[(2S,4S,6R)-6-methoxy-2-methyl-3-oxotetrahydro-2H-pyran-4-yl]acetamide | C9H12F3NO4 | 详情 | 详情 | |
| (VII) | 30695 | 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H14F3NO4 | 详情 | 详情 | |
| (VIII) | 30696 | N-[(2S,3R,4S,6R)-3,6-dihydroxy-2-methyltetrahydro-2H-pyran-4-yl]-2,2,2-trifluoroacetamide | C8H12F3NO4 | 详情 | 详情 | |
| (IX) | 66343 | 5-hydroxy-6-methyl-4-(2,2,2-trifluoroacetamido)tetrahydro-2H-pyran-2-yl 2,2,2-trifluoroacetate | C10H11F6NO5 | 详情 | 详情 | |
| (X) | 66344 | 2-oxo-2-(2,5,12-trihydroxy-4-((5-hydroxy-6-methyl-4-(2,2,2-trifluoroacetamido)tetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)ethyl acetate | C31H30F3NO13 | 详情 | 详情 | |
| (XI) | 66345 | 2,2,2-trifluoro-N-(3-hydroxy-2-methyl-6-((3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)tetrahydro-2H-pyran-4-yl)acetamide | C29H28F3NO12 | 详情 | 详情 | |
| (XII) | 30701 | 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-hydroxy-2-methyl-6-([(1S,3S)-3,5,12-trihydroxy-10-methoxy-3-[(4R)-4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl]-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy)tetrahydro-2H-pyran-4-yl]acetamide | C33H36F3NO13 | 详情 | 详情 |
合成路线2
| 【1】 Matvienko V, Matvyeyev A, et aL 2006. Epimerization of 4'-C bond and modification of 14-Me(CO)-fragment in anthracyclin antibiotics. W0 2006096665 |
| 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) | 66341 | (8S,10S)-8-acetyl-10-((4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione hydrochloride | C27H29NO10.HCl | 详情 | 详情 | |
| (II) | 66347 | 6-((3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)-2-methyl-4-(2,2,2-trifluoroacetamido)tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate | C31H27F6NO12 | 详情 | 详情 | |
| (III) | 66348 | N-(6-((3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)-2,2,2-trifluoroacetamide | C29H28F3NO11 | 详情 | 详情 | |
| (IV) | 66349 | N-(6-((3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)-2-methyl-3-oxotetrahydro-2H-pyran-4-yl)-2,2,2-trifluoroacetamide | C29H26F3NO11 | 详情 | 详情 | |
| (V) | 66350 | N-(6-((3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)-2,2,2-trifluoroacetamide | C29H28F3NO11 | 详情 | 详情 | |
| (VI) | 66351 | C27H29NO10.HCl | 详情 | 详情 |
合成路线3
A suspension of methyl 2,3,6-trideoxy-3-amino-alpha-L-lyxo-hexopyranoside (I) is acylated with trifluoroacetic anhydride in ether yielding methyl 2,3,6-trideoxy-3-trifluoroacetamido-alpha-L-lyxo-hexopyranoside (II), which is oxidized with potassium periodate and ruthenium dioxide in CH2Cl2 water to afford methyl 2,3,6-trideoxy-3-trifluoroacetamido-alpha-L-threo-hexapyranosid-4-ulose (III). The reduction of (III) with NaBH4 in dioxane-water gives methyl 2,3,6-trideoxy-3-trifluoroacetamido-alpha-L-arabino-hexopyranoside (IV), which is demethylated by treatment with aqueous acetic acid to yield 2,3,6-trideoxy-4-trifluoroacetamido-alpha-L-arabino-hexopyranose (V). Acylation of (V) with trifluoroacetic anhydride in ether affords 2,3,6-trideoxy-3-trifluoroacetamido-1,4-di-O-trifluoroacetyl-alpha-L-arabino-hexopyranose (VI), which by treatment with dry HCl in ether is converted into 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-L-arabino-hexopyranosyl chloride (VII). The condensation of (VII) with 9-deacetyl-9-(2',2'-dimethyl-4'-methoxydioxolan-4'-yl)daunomycinone (VIII) [prepared from adriamycinone (IX) and 2,2-dimethoxypropane-p-toluenesulfonic acid in dioxane - CHCl3] by means of HgO and HgBr2 in CH2Cl2 gives 4'-epi-3'-N-trifluoroacetyladriamycin protected in the hydroxylacetyl group (X). Finally, this compound is deprotected by treatment with NaOH in acetone water.
| 【1】 Franchi, G.; Formelli, F.; Redaelli, S.; Dasdia, T.; Soranzo, C.; Arcamone, F.; Penco, S.; Casazza, A.M.; Vigevani, A.; Di Marco, A.; Necco, A.; Synthesis and antitumor properties of new glycosides daunomycin and daunorubicin. J Med Chem 1975, 18, 7, 703-707. |
| 【2】 Serradell, M.N.; Castaner, J.; Hopkins, S.J.; Blancafort, P.; Epirubicin. Drugs Fut 1983, 8, 5, 402. |
| 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) | 30692 | (2S,3S,4S,6R)-4-amino-6-methoxy-2-methyltetrahydro-2H-pyran-3-ol | C7H15NO3 | 详情 | 详情 | |
| (II) | 30693 | 2,2,2-trifluoro-N-[(2S,3S,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H14F3NO4 | 详情 | 详情 | |
| (III) | 30694 | 2,2,2-trifluoro-N-[(2S,4S,6R)-6-methoxy-2-methyl-3-oxotetrahydro-2H-pyran-4-yl]acetamide | C9H12F3NO4 | 详情 | 详情 | |
| (IV) | 30695 | 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H14F3NO4 | 详情 | 详情 | |
| (V) | 30696 | N-[(2S,3R,4S,6R)-3,6-dihydroxy-2-methyltetrahydro-2H-pyran-4-yl]-2,2,2-trifluoroacetamide | C8H12F3NO4 | 详情 | 详情 | |
| (VI) | 30697 | (2S,3R,4S,6S)-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]-6-[(2,2,2-trifluoroacetyl)oxy]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate | C12H10F9NO6 | 详情 | 详情 | |
| (VII) | 30698 | (2S,3R,4S,6S)-6-chloro-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate | C10H10ClF6NO4 | 详情 | 详情 | |
| (VIII) | 30699 | (8S,10S)-6,8,10,11-tetrahydroxy-1-methoxy-8-[(4R)-4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl]-7,8,9,10-tetrahydro-5,12-naphthacenedione | C25H26O10 | 详情 | 详情 | |
| (IX) | 30700 | (8S,10S)-8-glycoloyl-6,8,10,11-tetrahydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C21H18O9 | 详情 | 详情 | |
| (X) | 30701 | 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-hydroxy-2-methyl-6-([(1S,3S)-3,5,12-trihydroxy-10-methoxy-3-[(4R)-4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl]-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy)tetrahydro-2H-pyran-4-yl]acetamide | C33H36F3NO13 | 详情 | 详情 |