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【结 构 式】 
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【分子编号】32205 【品名】1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine 【CA登记号】316-46-1 |
【 分 子 式 】C9H11FN2O6 【 分 子 量 】262.1946232 【元素组成】C 41.23% H 4.23% F 7.25% N 10.68% O 36.61% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be prepared by several different ways: 1) The reaction of 5-fluorouridine (I) with 2,2-dimethoxypropane (A) by means of p-toluenesulfonic acid gives 2',3'-isopropylidene-5-fluorouridine (III), which is treated with triphenylphosphite methiodide in DMF to afford 5'-deoxy-5'-iodo-2',3'-isopropylidene-5-fluorouridine (IV). The reduction of (IV) with H2 over Pd/C in methanol-triethyl-amine yields 5'-deoxy-2',3'-isopropylidene-5-fluorouridine (V), which is finally hydrolyzed with aqueous trifluoroacetic acid. 2) The hydrolysis of compound (IV) with aqueous trifluoroacetic acid as before gives 5'-deoxy-5'-iodouridine (II), which is finally reduced with H2 over Pd/C as before. 3) Compound (II) can also be obtained by reaction of (I) with triphenyl phosphite methiodide as before. 4) It can also be prepared via reduction of the 5'-chloro intermediate with tributyltin hydride.
| 【1】 Beranek, J.; Hrebabecky, H.; Analogs of nucleosides. XVI. 5'-Halo-2',3'-sulfites in the synthesis of 2',5'-dideoxy-5-fluorouridine and related analogs. Coll Czech Chem Commun 1978, 43, 15, 3268-78. |
| 【2】 Cook, A.F.; et al.; Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5'-deoxy-5-fluoropyrimidine nucleosides. J Med Chem 1979, 22, 11, 1330-35. |
| 【3】 Cook, A.F. (Hoffmann-La Roche, Inc.); 5'-Deoxy-5-fluoropyrimidine nucleosides. DE 2756653; ES 471584; FR 2374334; GB 1589688; JP 53095982; US 4071680 . |
| 【4】 Castaner, J.; Albonico, S.M.; Serradell, M.N.; Blancafort, P.; Doxifluridine. Drugs Fut 1981, 6, 2, 80. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (I) | 32205 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine | 316-46-1 | C9H11FN2O6 | 详情 | 详情 |
| (II) | 32206 | 1-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C9H10FIN2O5 | 详情 | 详情 | |
| (III) | 32207 | 2',3'-Isopropylidene-5-fluorouridine; 5-Fluoro-1-[(4R,6R)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C12H15FN2O6 | 详情 | 详情 | |
| (IV) | 32208 | 5-Fluoro-1-[(4R,6S)-6-(iodomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione; 5'-Deoxy-5'-iodo-2',3'-isopropylidene-5-fluorouridine | C12H14FIN2O5 | 详情 | 详情 | |
| (V) | 32209 | 5'-Deoxy-2',3'-isopropylidene-5-fluorouridine; 5-Fluoro-1-[(4R,6R)-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C12H15FN2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The bromoacetylation of 5-fluorouridine (I) with 2-acetoxyisobutyryl bromide (II) in acetonitrile, ethyl acetate or dichloromethane gives a mixture of four bromoacylated compounds (III), (IV), (V) and (VI). This mixture, without separation, is treated with Zn/Ac-OH in DMF or methanol/ethyl acetate to yield two unsaturated uridine derivatives (VII) and (VIII), which are easily separated. The major isomer (VIII) is condensed with 1,2,4-triazole (IX) by means of POCl3 and TEA in acetonitrile to afford the triazolyl derivative (X), which is treated with ammonia in methanol to provide the cytidine derivative (XI). Finally, this compound is deacylated by means of NaOMe in methanol to afford the target fluorocytidine derivative.
| 【1】 Confalone, P.N.; Jin, F. (Pharmasset, Inc.); Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides. WO 0270533 . |
| 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) | 32205 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine | 316-46-1 | C9H11FN2O6 | 详情 | 详情 |
| (II) | 12806 | 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide | 40635-67-4 | C6H9BrO3 | 详情 | 详情 |
| (III) | 58289 | {(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate | C17H20BrFN2O9 | 详情 | 详情 | |
| (IV) | 58290 | {(2R,4S,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate | C17H20BrFN2O9 | 详情 | 详情 | |
| (V) | 58291 | {(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate | C13H14BrFN2O7 | 详情 | 详情 | |
| (VI) | 58292 | {(2R,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate | C13H14BrFN2O7 | 详情 | 详情 | |
| (VII) | 58293 | {(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl acetate | C11H11FN2O5 | 详情 | 详情 | |
| (VIII) | 58294 | {(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate | C15H17FN2O7 | 详情 | 详情 | |
| (IX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (X) | 58295 | 2-({(2S,5R)-5-[5-fluoro-2-oxo-4-(1H-1,2,4-triazol-1-yl)-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate | C18H20FN5O5 | 详情 | 详情 | |
| (XI) | 58296 | 2-({(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate | C16H20FN3O5 | 详情 | 详情 |