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【结 构 式】 
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【药物名称】NSC-678516, FM-ara-U, FMAU 【化学名称】1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine 【CA登记号】69256-17-3 【 分 子 式 】C10H13FN2O5 【 分 子 量 】260.22391 |
【开发单位】Cornell University (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs |
合成路线1
FMAU is prepared by condensation of 3-O-benzoyl-2-fluoro-D-arabinosyl bromide (I) with trimethylsilylated thymine (II) followed by saponification of the protected nucleoside (III).
| 【1】 Lopez, C.; Reichman, U.; Fox, J.; Hirota, K.; Watanabe, K.A.; Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides. J Med Chem 1979, 22, 1, 21-24. |
| 【2】 Lopez, C.; Klein, R.S.; Su, T.L.; Fox, J.J.; Watanabe, K.A.; Matsuda, A.; Chun, M.W.; Chun, C.K.; Nucleosides. 123. Synthesis of sntiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships. J Med Chem 1983, 28, 2, 152-156. |
| 【3】 Lopez, C.; FMAU. Drugs Fut 1985, 10, 4, 288. |
| 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) | 29116 | [(2R,3R,4S,5S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C14H14BrFO5 | 详情 | 详情 | |
| (II) | 12218 | 5-Methyl-2,4-bis[(trimethylsilyl)methyl]pyrimidine | C13H26N2Si2 | 详情 | 详情 | |
| (III) | 29117 | [(2R,3R,4S,5R)-3-(acetoxy)-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C19H19FN2O7 | 详情 | 详情 |
合成路线2
The reaction of 1,3,5-tri-O-benzoyl-2-O-(trifluoromethanesulfonyl)-alpha-D-ribofuranose (I) with labeled tetrabutylammonium fluoride in acetonitrile gives 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (II), which is treated with HBr/HOAc in dichloroethane to yield 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (III). The condensation of (III) with thymine bis trimethylsilyl ether (IV) in dichloroethane affords a mixture of protected nucleoside alpha and beta anomers (V) and (VI), which, without separation, is deprotected with NaOMe in methanol and submitted to HPLC chromatographic separation to provide the target unprotected and labeled beta anomer.
| 【1】 Alauddin, M.M.; et al.; Synthesis of [18F]-labeled 2'-deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([18F]-FMAU). J Label Compd Radiopharm 2002, 45, 7, 583. |
| 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) | 56869 | (2R,3R,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-2-furanyl benzoate | C27H21F3O10S | 详情 | 详情 | |
| (II) | 17698 | [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C26H21FO7 | 详情 | 详情 | |
| (II) | 56870 | (2R,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-fluorotetrahydro-2-furanyl benzoate | C26H21FO7 | 详情 | 详情 | |
| (III) | 17524 | [(2S,3S,4R,5S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H16BrFO5 | 详情 | 详情 | |
| (III) | 56871 | (2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-5-bromo-4-fluorotetrahydro-3-furanyl benzoate | C19H16BrFO5 | 详情 | 详情 | |
| (IV) | 41900 | 5-methyl-2,4-bis[(trimethylsilyl)oxy]pyrimidine; 5-methyl-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether | 7288-28-0 | C11H22N2O2Si2 | 详情 | 详情 |
| (V) | 56872 | (2R,3R,4S,5S)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate | C24H21FN2O7 | 详情 | 详情 | |
| (V) | 56874 | (2R,3R,4S,5S)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate | C24H21FN2O7 | 详情 | 详情 | |
| (VI) | 56873 | (2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate | C24H21FN2O7 | 详情 | 详情 | |
| (VI) | 56875 | (2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate | C24H21FN2O7 | 详情 | 详情 |