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【结 构 式】 
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【分子编号】56701 【品名】[(3aR,5R,6S,6aR)-6-(benzoyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate 【CA登记号】 |
【 分 子 式 】C22H22O7 【 分 子 量 】398.41248 【元素组成】C 66.32% H 5.57% O 28.11% |
合成路线1
该中间体在本合成路线中的序号：(II)The acylation of 2,3-O-isopropylidene-alpha-D-xylofuranose (I) with benzoyl chloride and pyridine gives the dibenzoyl ester (II), which is deprotected by means of H2SO4/HOAc in hot THF to yield 3,5-di-O-benzoyl-alpha-D-xylofuranose (III). The reaction of (III) with PPh3, I2 and imidazole in dichloromethane affords the glycal (IV), which is used in the glycosylation of the N,O-disilylated 5-fluorocytosine (V) by means of NIS in dichloromethane to provide the 2'-alpha-iodonucleoside (VI). The treatment of (VI) with Zn in EtOH/ethyl acetate (HOAc is used as catalyst) gives the unsaturated nucleoside (VII), which is finally debenzoylated by means of butylamine in THF.
| 【1】 Chen, S.-H.; Lin, S.; King, I.; Spinka, T.; Dutschman, G.E.; Gullen, E.A.; Cheng, Y.-C.; Doyle, T.W.; Synthesis and comparative evaluation of two antiviral agents: beta-L-Fd4C and beta-D-Fd4C. Bioorg Med Chem Lett 1998, 8, 22, 3245. |
| 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) | 56701 | [(3aR,5R,6S,6aR)-6-(benzoyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C22H22O7 | 详情 | 详情 | |
| (III) | 56702 | [(2R,3R,4R,5S)-3-(benzoyloxy)-4,5-dihydroxytetrahydro-2-furanyl]methyl benzoate | C19H18O7 | 详情 | 详情 | |
| (IV) | 56703 | [(2R,3R)-3-(benzoyloxy)-2,3-dihydro-2-furanyl]methyl benzoate | C19H16O5 | 详情 | 详情 | |
| (V) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (VI) | 56704 | [(2R,3S,4R,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-3-(benzoyloxy)-4-iodotetrahydro-2-furanyl]methyl benzoate | C23H19FIN3O6 | 详情 | 详情 | |
| (VII) | 56705 | {(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl benzoate | C16H14FN3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)Reaction of L-xylose (XXII) with acetone and H2SO4 gives the acetonide (XXIII), which by acylation with benzoyl chloride in pyridine/chloroform yields the dibenzoate (XXIV). The hydrolysis of acetonide (XXIV) with acetic acid to the dihydroxy sugar (XXV) followed by acylation with acetic anhydride provides the tetracylated L-xylose (XXVI). Condensation of compound (XXVI) with 2,4-bis(trimethylsilyloxy)pyrimidine (XXVII) - obtained by silylation of uracil (XXVIII) with hexamethyldisilazane - by means of trimethylsilyl triflate in 1,2-dichloroethane affords nucleoside (XXIX). Selective hydrolysis of the acetate ester of compound (XXIX) using hydrazine and AcOH in pyridine yields the dibenzoylated xylofuranosyl-uracil (XXX). Isomerization of compound (XXX) to the arabinofuranosyl analogue (XXXI) is achieved by reaction with dicyclohexylcarbodiimide and dichloroacetic acid in DMSO/benzene, followed by treatment with NaBH4 in EtOH/benzene. Subsequent deoxygenation of the 2'-hy-droxyl group of compound (XXXI) to afford 2'-deoxynucleoside (XX) is effected via condensation with phenyl chlorothionoformate, and then reduction of the resulting thiocarbonate (XXXII) with tris(trimethylsilyl)silane and AIBN. Iodination of the uracil ring of (XX) with I2 and cerium ammonium nitrate (CAN) in acetonitrile produces the 5-iodo derivative (XXXIII), which is protected at the 3-nitrogen atom by condensation with p-toluoyl chloride to yield the protected nucleoside (XXXIV). Introduction of the 5-methyl group to give the thymidine derivative (XXXV) is then effected by reaction of the 5-iodouracil (XXXIV) with tetramethyltin in the presence of palladium catalyst. Finally, all protecting groups of compound (XXXV) are removed by treatment with methanolic ammonia.
| 【1】 Gosselin, G.; Bergogne, M.C.; Imbach, J.L.; Synthesis and antiviral evaluation of beta-L-xylo-furanosyl nucleosides of the five naturally occurring nucleic acid bases. J Heterocycl Chem 1993, 30, 5, 1229. |
| 【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 【3】 Gosselin, G.; Imbach, J.-L.; Aubertin, A.-M.; Sommadossi, J.-P.; Schinazi, R.F. (CNRS (Centre National de la Recherche Scientifique)); 2' or 3'-Deoxy and 2'-dideoxy-beta-L-pentafuranonucleoside cpds., method of preparation and application in therapy, especially as anti-viral agents. DE 2709754; EP 0717748; WO 9507287 . |
| 【4】 Bryant, M.L.; Gosselin, G.; Imbach, J.-L. (CNRS (Centre National de la Recherche Scientifique); Novirio Pharmaceuticals Ltd.); beta-L-2'-Deoxy-nucleosides for the treatment of hepatitis B. WO 0009531 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 39996 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O7 | 详情 | 详情 | |
| (XXII) | 62919 | (3S,4S,5S)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C5H10O5 | 详情 | 详情 | |
| (XXIII) | 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 |
| (XXIV) | 56701 | [(3aR,5R,6S,6aR)-6-(benzoyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C22H22O7 | 详情 | 详情 | |
| (XXV) | 56702 | [(2R,3R,4R,5S)-3-(benzoyloxy)-4,5-dihydroxytetrahydro-2-furanyl]methyl benzoate | C19H18O7 | 详情 | 详情 | |
| (XXVI) | 39991 | [(2S,3R,4S)-4,5-bis(acetoxy)-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C23H22O9 | 详情 | 详情 | |
| (XXVII) | 29619 | 2,4-bis[(trimethylsilyl)oxy]pyrimidine; trimethylsilyl 2-[(trimethylsilyl)oxy]-4-pyrimidinyl ether | C10H20N2O2Si2 | 详情 | 详情 | |
| (XXVIII) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (XXIX) | 39992 | (2S,3R,4S,5S)-4-(acetoxy)-2-[(benzoyloxy)methyl]-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate | C25H22N2O9 | 详情 | 详情 | |
| (XXX) | 39993 | [(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl]methyl benzoate | C23H20N2O8 | 详情 | 详情 | |
| (XXXI) | 39994 | [(2S,3R,4R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl]methyl benzoate | C23H20N2O8 | 详情 | 详情 | |
| (XXXII) | 39995 | [(2S,3S,4R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl benzoate | C30H24N2O9S | 详情 | 详情 | |
| (XXXIII) | 40002 | [(2S,3R,5S)-3-(benzoyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19IN2O7 | 详情 | 详情 | |
| (XXXIV) | 40003 | [(2S,3R,5S)-3-(benzoyloxy)-5-[5-iodo-3-(4-methylbenzoyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C31H25IN2O8 | 详情 | 详情 | |
| (XXXV) | 40004 | [(2S,3R,5S)-3-(benzoyloxy)-5-[5-methyl-3-(4-methylbenzoyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C32H28N2O8 | 详情 | 详情 |