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【结 构 式】 
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【药物名称】FTC-092 【化学名称】1-(3-O-Benzyl-2-deoxy-beta-D-ribofuranosyl)-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione 【CA登记号】96141-37-6 【 分 子 式 】C17H17F3N2O5 【 分 子 量 】386.33064 |
【开发单位】Taiho (Originator) 【药理作用】Oncolytic Drugs, Antimetabolites |
合成路线1
The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.
| 【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 . |
| 【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 . |
| 【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139. |
| 【4】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 31154 | 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione | 54-42-2 | C9H11IN2O5 | 详情 | 详情 |
| (II) | 31155 | [(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C16H15IN2O6 | 详情 | 详情 | |
| (III) | 31156 | benzyl 2,2,2-trichloroethanimidoate | 81927-55-1 | C9H8Cl3NO | 详情 | 详情 |
| (IV) | 31157 | [(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H21IN2O6 | 详情 | 详情 | |
| (V) | 31158 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione | C16H17IN2O5 | 详情 | 详情 | |
| (IX) | 11875 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine | 951-78-0 | C9H12N2O5 | 详情 | 详情 |
| (X) | 31159 | 1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C28H26N2O5 | 详情 | 详情 | |
| (XI) | 31160 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C35H32N2O5 | 详情 | 详情 | |
| (XII) | 31161 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione | C36H31F3N2O5 | 详情 | 详情 |
合成路线2
The benzoylation of 2'-deoxy-5-(trifluoromethyl)uridine (VI) with benzoyl chloride by means of triethylamine in dimethylacetamide gives 3-benzoyl-2'-deoxy-5-(trifluoromethyl)uridine (VII), which is benzylated with benzyl bromide and silver oxide in refluxing 2-butanone to afford 3-benzoyl-3'-O-benzyl-2'-deoxy-5-(trifluoromethyl)uridine (VIII). Finally, this compound is debenzoylated with 30% aqueous ammonia at room temperature. The deprotection of 2'-deoxy-3'-O-(thiobenzoyl)-5-(trifluoromethyl)-5'-O-trityluridine (XIII) with 0.1N HCl gives 2'-deoxy-3'-O-(thiobenzoyl)-5-(trifluoromethyl)uridine (XIV), which is submitted to desulfurization with Raney-Ni in THF.
| 【1】 Noguchi, K.; Yasumoto, M.; Kobayashi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 5-trifluromethyl-2'-deoxy-beta-uridines. JP 1988145296 . |
| 【2】 Yamashita, J.-I.; Matsumoto, H.; Kobayashi, K.; Noguchi, K.; Yasumoto, M.; Ueda, T.; Studies on antitumor agents. IX. Synthesis of 3'-O-benzyl-2'-deoxy-5-trifluromethyluridine. Chem Pharm Bull 1989, 37, 9, 2287-92. |
| 【3】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (VI) | 31162 | 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione | 70-00-8 | C10H11F3N2O5 | 详情 | 详情 |
| (VII) | 31163 | 3-benzoyl-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione | C17H15F3N2O6 | 详情 | 详情 | |
| (VIII) | 31164 | 3-benzoyl-1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione | C24H21F3N2O6 | 详情 | 详情 | |
| (XIII) | 31165 | O-[(2R,3S,5R)-5-[2,4-dioxo-5-(trifluoromethyl)-3,4-dihydro-1(2H)-pyrimidinyl]-2-[(trityloxy)methyl]tetrahydro-3-furanyl] benzenecarbothioate | C36H29F3N2O5S | 详情 | 详情 | |
| (XIV) | 31166 | O-[(2R,3S,5R)-5-[2,4-dioxo-5-(trifluoromethyl)-3,4-dihydro-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl] benzenecarbothioate | C17H15F3N2O5S | 详情 | 详情 |