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【结 构 式】 
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【分子编号】30921 【品名】2,4(1H,3H)-pyrimidinedione; Uracil 【CA登记号】66-22-8 |
【 分 子 式 】C4H4N2O2 【 分 子 量 】112.08804 【元素组成】C 42.86% H 3.6% N 24.99% O 28.55% |
合成路线1
该中间体在本合成路线中的序号：(VI)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)Uracil (I) was silylated with hexamethyldisilazan, and the resulting bis-silylated uracil (II) was condensed with protected xylofuranose (III) in the presence of trimethylsilyl triflate to afford nucleoside (IV). Selective hydrolysis of the acetate ester of (IV) employing hydrazine and AcOH in pyridine yielded (V). Isomerization of xylofuranosyl uracil (V) to the arabinofuranosyl analogue (VI) was achieved by reaction with dicyclohexylcarbodiimide and dichloroacetic acid followed by treatment with NaBH4. Subsequent deoxygenation of the 2'-hydroxyl group of (VI) was effected via condensation with phenyl chlorothionoformate, and then reduction of the resulting thiocarbonate (VII) with tris(trimethylsilyl)silane and azobis(isobutyronitrile) (AIBN). The resultant 2'-deoxyuridine derivative (VIII) was treated with Lawesson's reagent to give the thiocarbonyl analogue (IX). Finally, sulfur displacement with concomitant benzoate ester hydrolysis employing methanolic ammonia at 100 C in a pressure bomb furnished the title compound.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (II) | 29619 | 2,4-bis[(trimethylsilyl)oxy]pyrimidine; trimethylsilyl 2-[(trimethylsilyl)oxy]-4-pyrimidinyl ether | C10H20N2O2Si2 | 详情 | 详情 | |
| (III) | 39991 | [(2S,3R,4S)-4,5-bis(acetoxy)-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C23H22O9 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 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 | |
| (VI) | 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 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 40005 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVIII)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 |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of the epoxy-glucoside (I) with Tms-N3 in DMF gives the azido-glucoside (II), which is treated with Pmb-Cl and NaH in DMF to yield the aryl ether protected glucoside (III). The cleavage of the acetonide group of (III) by means of HOAc/water affords the dihydroxy compound (IV), which is acylated by means of Ac2O and pyridine to provide the diacetate (V). The condensation of (V) with uracil (VI) by means of BSA and Tms-Br in acetonitrile gives the uridine derivative (VII), which is reduced at its azido group by means of H2 over Pd/C in ethyl acetate to yield the amino derivative (VIII). The condensation of (VIII) with palmitic anhydride (IX) affords the corresponding amide (X), which is selectively deprotected by means of TFA to provide the alcohol (XI). The condensation of (XI) with 5-azido-5-deoxy-1,2,3-O-triacetyl-alpha-D-ribofuranose (XII) by means of SnCl4 in dichloromethane provides the uridine derivative (XIII), which is deacetylated by means of MeONa in methanol to give the azido precursor (XIV). Finally, the azido group of (XIV) is reduced by means of H2 over Pd/C in methanol to yield the target compound.
| 【1】 Dini, C.; et al.; Synthesis and in vitro evaluation of riburamycin RU75411: Activity against MraY, antibacterial profile, and mechanism of action (MOA) on whole cells. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-361. |
| 【2】 Aszodi, J.; Didierlaurent, S.; Dini, C.; Zhang, J.; Drochon, N.; Guillot, J.-C. (Aventis Pharma SA); Uridine derivs. as antibiotics. EP 1284984; WO 0185750 . |
| 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) | 58679 | (3aR,5S,6aR)-2,2-dimethyl-5-[(2S)oxiranyl]tetrahydrofuro[2,3-d][1,3]dioxole | C9H14O4 | 详情 | 详情 | |
| (II) | 58680 | (1S)-1-[(3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-azido-1-ethanol | C9H15N3O4 | 详情 | 详情 | |
| (III) | 58681 | (3aR,5S,6aR)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; (1S)-1-[(3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-azidoethyl 4-methoxybenzyl ether | C17H23N3O5 | 详情 | 详情 | |
| (IV) | 58682 | (2S,3R,5S)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}tetrahydro-2,3-furandiol | C14H19N3O5 | 详情 | 详情 | |
| (V) | 58683 | (2R,3R,5S)-2-(acetyloxy)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}tetrahydro-3-furanyl acetate | C18H23N3O7 | 详情 | 详情 | |
| (VI) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (VII) | 58684 | (2R,3R,5S)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C20H23N5O7 | 详情 | 详情 | |
| (VIII) | 58685 | (2R,3R,5S)-5-{(1S)-2-amino-1-[(4-methoxybenzyl)oxy]ethyl}-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C20H25N3O7 | 详情 | 详情 | |
| (IX) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
| (X) | 58686 | (2R,3R,5S)-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[(1S)-1-[(4-methoxybenzyl)oxy]-2-(palmitoylamino)ethyl]tetrahydro-3-furanyl acetate | C36H55N3O8 | 详情 | 详情 | |
| (XI) | 58687 | (2R,3R,5S)-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[(1S)-1-hydroxy-2-(palmitoylamino)ethyl]tetrahydro-3-furanyl acetate | C28H47N3O7 | 详情 | 详情 | |
| (XII) | 58688 | (2R,3R,4R,5R)-2,4-bis(acetyloxy)-5-(azidomethyl)tetrahydro-3-furanyl acetate | C11H15N3O7 | 详情 | 详情 | |
| (XIII) | 58689 | (2R,3R,4R,5S)-4-(acetyloxy)-5-{[(1S)-1-{(2S,4R,5R)-4-(acetyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}-2-(palmitoylamino)ethyl]oxy}-2-(azidomethyl)tetrahydro-3-furanyl acetate | C37H58N6O12 | 详情 | 详情 | |
| (XIV) | 58690 | N-((2S)-2-{[(2R,3R,4S,5R)-5-(azidomethyl)-3,4-dihydroxytetrahydro-2-furanyl]oxy}-2-{(2S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl}ethyl)hexadecanamide | C31H52N6O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Alkylation of uracil (I) with propargyl bromide (II) in the presence of DBU affords the N1-alkylated product (III). Palladium-catalyzed coupling of the terminal alkyne (III) with cis-1,2-dichloroethene (IV) furnishes the chlorovinyl adduct (V). Subsequent alkylation at the N3-position of (V) with propargyl bromide (II) and DBU leads to the open-chain enediyne (VI). This is finally cyclized to the target bicyclic compound in the presence of Pd(PPh3)4, CuI and butylamine.
| 【1】 Hakimelahi, G.H.; et al.; A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics. Bioorg Med Chem 2002, 10, 5, 1321. |
| 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) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (II) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (III) | 60461 | 1-(2-propynyl)-2,4(1H,3H)-pyrimidinedione | C7H6N2O2 | 详情 | 详情 | |
| (IV) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (V) | 60462 | 1-[(Z)-5-chloro-4-penten-2-ynyl]-2,4(1H,3H)-pyrimidinedione | C9H7ClN2O2 | 详情 | 详情 | |
| (VI) | 60463 | 1-[(Z)-5-chloro-4-penten-2-ynyl]-3-(2-propynyl)-2,4(1H,3H)-pyrimidinedione | C12H9ClN2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Iodination of 2-tert-butylphenol (I) with excess NaI and NaOCl in the presence of NaOH in MeOH gives 2-tert-butyl-4,6-diiodophenol (II), which is O-alkylated with Me2SO4 and K2CO3 or with MeI and NaOH in refluxing acetone to yield 1-tert-butyl-3,5-diiodo-2-methoxybenzene (III). goldberg reaction of aryl iodide (III) with uracil (Iv) by means of CuI, K3PO4 and N-(2-cyanophenyl)picolinamide in DMSO at 60 °C affords 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil (v) (1-4), which by Suzuki coupling with 6-hydroxy-2-naphthylboronic acid (vI) in the presence of Pd2dba3, K3PO4 and meCgPPh (1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.113,7]decane) in THF provides adduct (vII). Condensation of naphthol (vII) with perfluoro-butanesulfonyl fluoride (vIII) and K2CO3 in acetonitrile/DMF produces sulfonate (IX), which is finally condensed with methanesulfonamide (X) using Pd2dba3, K3PO4 and t-BuBrettPhos in t-amyl alcohol at 60 °C, THF, 2-MeTHF or EtOAc .
In a related procedure, dasabuvir is obtained by Suzuki coupling of aryl iodide (v) with pinacol 6-(methylsulfonamido)-2-naphth-ylboronate (XI) using K3PO4, Pd2dba3 and meCgPPh in THF/H2O at 50 °C .
| 【1】 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146. |
| 【3】 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134. |
| 【4】 Shekhar, S., Franczyk, T.S., Barnes, D.M., Dunn, T.B., Haight, A.R., Chan, v.S. (Abbvie, Inc.) Process for preparing antiviral compounds. CN 103097360, EP 2593439, JP 2013532636, KR 2013043195, US 2012014913, WO 2012009699. |
| 【2】 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127. |
| 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) | 67678 | 2-tert-butylphenol；o-t-Butylphenol；o-tert-Butylphenol；2-tert-Butyl-1-hydroxybenzene；2-(1,1-Dimethylethyl)phenol | 88-18-6 | C10H14O | 详情 | 详情 |
| (II) | 67679 | 2-tert-butyl-4,6-diiodophenol | C10H12I2O | 详情 | 详情 | |
| (III) | 67680 | 1-tert-butyl-3,5-diiodo-2-methoxybenzene | C11H14I2O | 详情 | 详情 | |
| (IV) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (V) | 67681 | 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil | C15H17IN2O3 | 详情 | 详情 | |
| (VI) | 67682 | 6-hydroxy-2-naphthylboronic acid | 173194-95-1 | C10H9BO3 | 详情 | 详情 |
| (VII) | 67683 | 1-(3-(tert-butyl)-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione | C25H24N2O4 | 详情 | 详情 | |
| (VIII) | 67684 | perfluoro-butanesulfonyl fluoride | 375-72-4 | C4F10O2S | 详情 | 详情 |
| (IX) | 67685 | 6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate | C29H23F9N2O6S | 详情 | 详情 | |
| (X) | 39701 | methanesulfonamide | 3144-09-0 | CH5NO2S | 详情 | 详情 |
| (XI) | 67686 | N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide | C17H22BNO4S | 详情 | 详情 |