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【结 构 式】 
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【分子编号】30917 【品名】[(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol 【CA登记号】 |
【 分 子 式 】C23H28O6 【 分 子 量 】400.47172 【元素组成】C 68.98% H 7.05% O 23.97% |
合成路线1
该中间体在本合成路线中的序号：(II)The benzylation of 4-C-(hydroxymethyl)-1,2-isopropylidene-alpha-D-ribofuranose (I) with benzyl bromide and NaH in DMF gives the 3,5-di-O-benzyl derivative (II), which is treated with I2, imidazole and triphenylphosphine in refluxing toluene/acetonitrile yielding the iodomethyl derivative (III). The deiodination of (III) with tributyltin hydride and AIBN in hot toluene affords the 4-C-methyl compound (IV), which is treated with acetic anhydride and H2SO4 in acetic acid to give the 1,2-di-O-acetyl derivative (V). The condensation of (V) with uracil (VI) by means of TMS-OTf yields the uridine derivative (VII), which is deprotected first by deacetylation with ammonia and then by debenzylation with H2 over Pd/C affording the 4'-C-methyl-uridine (VIII). The reaction of (VIII) with acetyl bromide in refluxing acetonitrile gives the acetylated 2'-bromo derivative (IX), which is debrominated with tributyltin hydride and AIBN in hot toluene yielding 3',5'-O-diacetyl-2'-deoxy-4'-C-methyl-uridine (X). The iodination of (X) with I2 and ceric ammonium nitrate (CAN) affords the 5-iodo derivative (XI), which is condensed with methyl acrylate by means of Pd(OAc)2 and triphenylphosphine in dioxane giving the methoxycarbonylvinyl derivative (XII). The hydrolysis of (XII) with NaOH in methanol yields 5-(2(E)-carboxyvinyl)-2'-deoxy-4'-C-methyl-uridine (XIII), which is finally submitted to a decarboxylative bromination with N-bromosuccinimide ans KHCO3 in DMF.
| 【1】 Waga, T.; et al.; Synthesis of 4'-C-methylnucleosides. Biosci Biotech Biochem 1993, 57, 9, 1433-38. |
| 【2】 Waga, T.; et al.; Synthesis and biological evaluation of 4'-C-methylnucleosides. Nucleosides Nucleotides 1996, 15, 1-3, 287-304. |
| 【3】 Machida, H.; Kitano, K.; Miura, S.; Synthesis of novel 4'-C-methyl-pyrimidine nucleosides and their biological activities. Bioorg Med Chem Lett 1999, 9, 6, 827. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 | |
| (I) | 30916 | [(3aR,6S,6aR)-6-(benzyloxy)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol | C16H22O6 | 详情 | 详情 | |
| (II) | 30917 | [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol | C23H28O6 | 详情 | 详情 | |
| (III) | 30918 | (3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether | C23H27IO5 | 详情 | 详情 | |
| (IV) | 30919 | (3aR,5S,6S,6aR)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl benzyl ether; (3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxole | C23H28O5 | 详情 | 详情 | |
| (V) | 30920 | (2S,3R,4S,5S)-2-(acetoxy)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-methyltetrahydro-3-furanyl acetate | C24H28O7 | 详情 | 详情 | |
| (VI) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (VII) | 30922 | (2R,3R,4S,5S)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-methyltetrahydro-3-furanyl acetate | C26H28N2O7 | 详情 | 详情 | |
| (VIII) | 30923 | 1-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C10H14N2O6 | 详情 | 详情 | |
| (IX) | 30924 | [(2S,3R,4R,5R)-3-(acetoxy)-4-bromo-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate | C14H17BrN2O7 | 详情 | 详情 | |
| (X) | 30925 | [(2S,3S,5R)-3-(acetoxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate | C14H18N2O7 | 详情 | 详情 | |
| (XI) | 30926 | [(2S,3S,5R)-3-(acetoxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate | C14H17IN2O7 | 详情 | 详情 | |
| (XII) | 30927 | methyl (E)-3-(1-[(2R,4S,5S)-4-(acetoxy)-5-[(acetoxy)methyl]-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-2-propenoate | C18H22N2O9 | 详情 | 详情 | |
| (XIII) | 30928 | (E)-3-[1-[(2R,4S,5S)-4-hydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoic acid | C13H16N2O7 | 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 oxidation of the hydroxymethyl group of 3,5-di-O-benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-alpha-D-ribo-pentofuranose (I) with oxalyl chloride and TEA in DMSO gives the aldehyde (II), which is treated with CBr4 and PPH3 in dichloromethane to yield the dibromovinyl compound (III). The reaction of (III) with BuLi in THF affords the ethynyl derivative (IV), which is silylated with Tes-Cl and BuLi in THF to provide the triethylsilylethynyl compound (V). Elimination of the acetonide group of (V) with HOAc and TFA gives the dihydroxycompound (VI), which is treated with Ac2O and pyridine, yielding the diacetate (VII). The condensation of the sugar(VII) with 5-fluorouracil (VIII) by means of Tms-OTf and N,O-bis(trimethylsilyl)acetamide in dichloroethane affords the adduct (IX), which is deacetylated with TEA in methanol to provide the hydroxy derivative (X). The debenzylation of (X) by means of BCl3 in dichloromethane furnishes the trihydroxy compound (XI), which is treated with acetyl bromide in acetonitrile to give the bromo diacetoxy derivative (XII). The debromination of (XII) is performed with Bu3SnH and AIBN in hot toluene, yielding the diacetate (XIII), which is condensed with 1,2,4-triazole (XIV) by means of 4-chlorophenyl dichlorophosphate in pyridine to afford the triazolopyrimidinone (XV). Finally, (XV) is converted into the target compound by cleavage of the triazole ring with NH4OH in dioxane and deacetylation with NaOH in methanol/water.
| 【1】 Kohgo, S.; Kitano, K.; Ohrui, H.; et al.; Synthesis of 4'-C-ethynyl-beta-D-arabino-and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity. J Med Chem 2000, 43, 23, 4516. |
| 【2】 Matsuoka, M.; Kodama, E.; Kitano, K.; Kohgo, S.; Mitsuya, H.; Ohrui, H. (Yamasa Shoyu Co., Ltd.); 4'-C-Ethynyl purine nucleosides. WO 0069876; WO 0069877 . |
| 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) | 30917 | [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol | C23H28O6 | 详情 | 详情 | |
| (II) | 46262 | (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde | C23H26O6 | 详情 | 详情 | |
| (III) | 46263 | (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(3aR,5R,6S,6aR)-6-(benzyloxy)-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether | C24H26Br2O5 | 详情 | 详情 | |
| (IV) | 46264 | [(3aR,5R,6S,6aR)-6-(benzyloxy)-5-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether; (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole | C24H26O5 | 详情 | 详情 | |
| (V) | 46265 | [(3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyl-5-[2-(triethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether; (2-[(3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethynyl)(triethyl)silane | C30H40O5Si | 详情 | 详情 | |
| (VI) | 46266 | (2S,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-2,3-furandiol | C27H36O5Si | 详情 | 详情 | |
| (VII) | 46267 | (2R,3R,4S,5R)-2-(acetoxy)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-3-furanyl acetate | C31H40O7Si | 详情 | 详情 | |
| (VIII) | 29341 | (6R,9S,12S)-6-(cyclohexylmethyl)-12-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(1H-indol-3-ylmethyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C38H53N7O8S | 详情 | 详情 | |
| (IX) | 46268 | (2R,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-3-furanyl acetate | C33H39FN2O7Si | 详情 | 详情 | |
| (X) | 46269 | 1-[(2R,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-3-hydroxy-5-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C31H37FN2O6Si | 详情 | 详情 | |
| (XI) | 46270 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-5-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C17H25FN2O6Si | 详情 | 详情 | |
| (XII) | 46271 | [(2R,3R,4R,5R)-3-(acetoxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate | C21H28BrFN2O7Si | 详情 | 详情 | |
| (XIII) | 46272 | [(2R,3S,5R)-3-(acetoxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate | C21H29FN2O7Si | 详情 | 详情 | |
| (XIV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XV) | 46273 | [(2R,3S,5R)-3-(acetoxy)-5-[5-fluoro-2-oxo-4-(1H-1,2,4-triazol-1-yl)-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate | C23H30FN5O6Si | 详情 | 详情 |