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【结 构 式】 
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【分子编号】47859 【品名】5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine 【CA登记号】17242-85-2 |
【 分 子 式 】C10H19FN2O2Si2 【 分 子 量 】274.4425432 【元素组成】C 43.77% H 6.98% F 6.92% N 10.21% O 11.66% Si 20.47% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.
| 【3】 Gullen, E.; Zhu, Y.-L.; Liu, M.-C.; Dutschman, G.E.; Cheng, Y.-C.; Luo, M.-Z.; Lin, T.-S.; Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human. J Med Chem 1996, 39, 9, 1757. |
| 【1】 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072. |
| 【2】 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131. |
| 【4】 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 56917 | alpha-L-arabinofuranose | C5H10O5 | 详情 | 详情 | |
| (XIV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (XV) | 56918 | (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol | C6H10N2O4 | 详情 | 详情 | |
| (XVI) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XVII) | 39999 | (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one | 3736-77-4 | C9H10N2O5 | 详情 | 详情 |
| (XVIII) | 56919 | 2-oxo-2-phenylacetonitrile | C8H5NO | 详情 | 详情 | |
| (XIX) | 40000 | [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate | C23H18N2O7 | 详情 | 详情 | |
| (XX) | 40001 | [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19ClN2O7 | 详情 | 详情 | |
| (XXI) | 56920 | {(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-iodotetrahydro-2-furanyl}methyl benzoate | C23H19IN2O7 | 详情 | 详情 | |
| (XXII) | 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 | |
| (XXIII) | 47859 | 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine | 17242-85-2 | C10H19FN2O2Si2 | 详情 | 详情 |
| (XXIV) | 56921 | {(2S,3R,5S)-3-(benzoyloxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate | C23H19FN2O7 | 详情 | 详情 | |
| (XXV) | 54714 | 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C9H11FN2O5 | 详情 | 详情 | |
| (XXVI) | 54709 | {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate | C11H15FN2O9S2 | 详情 | 详情 | |
| (XXVII) | 54710 | [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate | C10H11FN2O6S | 详情 | 详情 | |
| (XXVIII) | 54711 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C9H9FN2O4 | 详情 | 详情 | |
| (XXIX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXX) | 54712 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone | C11H10FN5O3 | 详情 | 详情 | |
| (XXXI) | 54713 | 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone | C9H10FN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIII)Condensation of the chiral lactone (IV) with 2,4,6-tris-isopropylphenylsulfanyl chloride (XXXII) by means of LiHMDS and TMS-OTf in THF gives the adduct (XXXIII), which is reduced with DIBAL in toluene to yield the lactol (XXXIV). Reaction of compound (XXXIV) with Ac2O and pyridine in THF affords the acetoxy derivative (XXXV), which is condensed with the silylated 5-fluorouracil (XXIII) by means of SnCl4 in dichloromethane to provide the nucleoside (XXXVI). Oxidation of the sulfanyl group of (XXXVI) with magnesium monoperoxyphthalate (MMPP) in THF, followed by desulfurization by heating with DBU in refluxing toluene, gives 5'-O-TBDPS-2',3'-dideoxy-2',3'-didehydro-5-fluoro-b-L-uridine (XXXVII), which by treatment with Bu4NF in THF yields 2',3'-dideoxy-2',3'-didehydro-b-L-uridine (XXXIX). Finally, this compound is converted into 2',3'-dideoxy-2',3'-didehydro-b-L-cytidine by conventional methods.
| 【1】 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131. |
| 【2】 Schinazi, R.F.; Liotta, D.C. (Emory University); [5-Carboxamido or 5-fluoro]-[2',3'-unsaturated or 3'-modified]-pyrimidine nucleosides. EP 0805683; JP 1998512887; US 5703058; WO 9622778 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 56922 | (5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)dihydro-2(3H)-furanone | C21H26O3Si | 详情 | 详情 | |
| (XXIII) | 47859 | 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine | 17242-85-2 | C10H19FN2O2Si2 | 详情 | 详情 |
| (XXXII) | 56923 | 2,4,6-triisopropylbenzenesulfenyl chloride | C15H23ClS | 详情 | 详情 | |
| (XXXIII) | 56924 | (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]dihydro-2(3H)-furanone | C36H48O3SSi | 详情 | 详情 | |
| (XXXIV) | 56925 | (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanol | C36H50O3SSi | 详情 | 详情 | |
| (XXXV) | 56926 | (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanyl acetate | C38H52O4SSi | 详情 | 详情 | |
| (XXXVI) | 56927 | 1-{(2S,3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanyl}-5-fluoro-2,4(1H,3H)-pyrimidinedione | C40H51FN2O4SSi | 详情 | 详情 | |
| (XXXVII) | 56928 | 1-[(2S,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,5-dihydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C25H27FN2O4Si | 详情 | 详情 | |
| (XXXIX) | 56929 | 5-fluoro-1-[(2S,5R)-5-(hydroxymethyl)-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C9H9FN2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Catalytic hydrogenation of dihydrofuranone (I) over Pd/C afforded the saturated lactone (II). Treatment of (II) with chlorotrimethylsilane and lithium hexamethyldisilazide produced the silyl enol ether (III) which, without isolation, was treated with phenylselenenyl bromide to yield the trans-selenide (IV). Lactone reduction by means of DIBAL followed by acetylation of the resulting lactol (Va-b) gave acetate (VIa-b). The glycosylation of the silylated fluorouracil (VII) with (VIa-b) in the presence of trimethylsilyl triflate furnished adduct (VIIIa-b). Subsequent oxidative elimination of the phenylselenenyl group of (VIIIa-b) via an intermediate selenoxide produced the dihydrofuran derivative (IX), which was finally desilylated by treatment with tetrabutylammonium fluoride.
| 【1】 Kim, H.O.; Moon, H.R.; Lee, C.-K.; Jeong, L.S.; Choi, W.J.; Chun, M.W.; Hong, J.H.; Yoo, S.J.; Synthesis and structure-activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents. J Med Chem 2001, 44, 5, 806. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 47855 | (2R,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanol | C27H32O3SeSi | 详情 | 详情 | |
| (Vb) | 47856 | (2S,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanol | C27H32O3SeSi | 详情 | 详情 | |
| (VIa) | 47857 | (2S,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl acetate | C29H34O4SeSi | 详情 | 详情 | |
| (VIb) | 47858 | (2R,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl acetate | C29H34O4SeSi | 详情 | 详情 | |
| (VIIIa) | 47860 | 1-[(2R,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C31H33FN2O4SeSi | 详情 | 详情 | |
| (VIIIb) | 47861 | 1-[(2S,3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C31H33FN2O4SeSi | 详情 | 详情 | |
| (I) | 47851 | 4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2(5H)-furanone | C21H24O3Si | 详情 | 详情 | |
| (II) | 47852 | 4-([[tert-butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C21H26O3Si | 详情 | 详情 | |
| (III) | 47853 | tert-butyl(diphenyl)silyl [5-[(trimethylsilyl)oxy]-2,3-dihydro-3-furanyl]methyl ether; [[4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4,5-dihydro-2-furanyl]oxy](trimethyl)silane | C24H34O3Si2 | 详情 | 详情 | |
| (IV) | 47854 | (3S,4S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)dihydro-2(3H)-furanone | C27H30O3SeSi | 详情 | 详情 | |
| (VII) | 47859 | 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine | 17242-85-2 | C10H19FN2O2Si2 | 详情 | 详情 |
| (IX) | 47862 | 1-[4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C25H27FN2O4Si | 详情 | 详情 |