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【结 构 式】 
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【分子编号】54396 【品名】(3aR,5R,6R,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-ol 【CA登记号】 |
【 分 子 式 】C19H36O5Si2 【 分 子 量 】400.66284 【元素组成】C 56.96% H 9.06% O 19.97% Si 14.02% |
合成路线1
该中间体在本合成路线中的序号：(V)The selective protection of 1,2-O-isopropylidene-D-xylofuranose (I) with Tbdms-Cl and pyridine gives the silyl ether (II), which is oxidized with CrO3, pyridine and Ac2O in dichloromethane to yield the ketone (III). Stereoselective addition of trimethylsilylacetylene (IV) to the ketone (III) by means of BuLi in THF affords the beta-adduct (V), which is desilylated by means of TBAF in THF to provide 3-C-ethynyl-2,3-o-isopropylidene-alpha-D-ribofuranose (VI). The selective monobenzoylation of (VI) with benzoyl chloride and pyridine gives the monobenzoate (VII), which is treated with HCl in methanol to cleave the isopropylidene protecting group and yield (VIII). The exhaustive benzoylation of (VIII) with benzoyl chloride and DMAP in pyridine at 100 C affords the tribenzoate (IX), which is treated with H2SO4 and Ac2O to provide the monoacetate (X). The condensation of (X) with cytosine (XI) by means of SnCl4 in acetonitrile gives the cytidine derivative (XII), which is finally debenzoylated by means of NH3 in methanol to yield the target ethynyl-cytidine derivative.
| 【1】 Nomura, M.; Sato, T.; Masato, W.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A.; Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbruggen glycosylation . Tetrahedron 2002, 58, 7, 1279. |
| 【3】 Hattori, H.; et al.; Nucleosides and nucleotides. 158. 1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil, and their nucleobase analogues as new potential multifunctional antitumor nucleosides with a broad spectrum of activity. J Med Chem 1996, 39, 25, 5005. |
| 【2】 Nozawa, E.; Hattori, H.; Shuto, S.; Tanaka, M.; Sasaki, T.; Matsuda, A.; Synthesis and antitumor activity of 1-(3-C-ethynyl-beta-D-ribo-pentfuranosyl)cytosine, -uracil and their sugar modified derivatives. Nucleic Acids Symp Ser 1996, 35, 31. |
| 【4】 Matsuda, A.; Sasaki, T. (Taiho Pharmaceutical Co., Ltd.); 3'-Substd. nucleoside derivs.. EP 0747389; WO 9618636 . |
| 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) | 41907 | (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | 20031-21-4 | C8H14O5 | 详情 | 详情 |
| (II) | 54394 | (3aR,5R,6S,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | C14H28O5Si | 详情 | 详情 | |
| (III) | 54395 | (3aR,5R,6aS)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one | C14H26O5Si | 详情 | 详情 | |
| (IV) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (V) | 54396 | (3aR,5R,6R,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-ol | C19H36O5Si2 | 详情 | 详情 | |
| (VI) | 54397 | (3aR,5R,6R,6aR)-6-ethynyl-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | C10H14O5 | 详情 | 详情 | |
| (VII) | 54398 | [(3aR,5R,6R,6aR)-6-ethynyl-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C17H18O6 | 详情 | 详情 | |
| (VIII) | 54399 | [(2R,3S,4R,5S)-3-ethynyl-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate | C15H16O6 | 详情 | 详情 | |
| (IX) | 54400 | [(2R,3R,4R,5S)-3,4-bis(benzoyloxy)-3-ethynyl-5-methoxytetrahydro-2-furanyl]methyl benzoate | C29H24O8 | 详情 | 详情 | |
| (X) | 54401 | [(2R,3R,4R,5R)-5-(acetyloxy)-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate | C30H24O9 | 详情 | 详情 | |
| (XI) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XII) | 54402 | [(2R,3R,4R,5R)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate | C32H25N3O8 | 详情 | 详情 |