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【结 构 式】 
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【分子编号】12795 【品名】(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine 【CA登记号】58-63-9 |
【 分 子 式 】C10H12N4O5 【 分 子 量 】268.22924 【元素组成】C 44.78% H 4.51% N 20.89% O 29.82% |
合成路线1
该中间体在本合成路线中的序号：(I)3) The reaction of inosine (I) with tert-butyldimethylsilyl chloride by means of imidazole in DMF gives the 5'-O-silyl derivative (II), which by reaction with CS2 and 3-bromopropionitrile by means of NaOH in DMSO is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-(2-cyanoethyldithiocarbonyl)inosine (III). The reaction of (III) with tri-n-butyltin hydride and AIBN in refluxing toluene affords 5'-O-(tert-butyldimethylsilyl-2',3'-dideoxy-2',3'-didehydroinosine (IV), which is deprotected with tetrabutylammonium fluoride in THF to 2',3'-dideoxy-2',3'-didehydroinosine (V). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol - water. 4) The reaction of (II) with 1,1'-thiocarbonyldiimidazole (DTI) in DMF gives 5'-O-(tert-butyldimethylsilyl)-2',3'-O-(thionocarbonyl)inosine (VI), which by reaction with refluxing triethyl phosphite is converted into the didehydro derivative (IV), already obtained (5).
| 【1】 Webb, R.R. II, Wos, J.A.; Martin, J.C.; Brodfuehrer, P.R.; Synthesis of 2',3'-dideoxyinosine. Nucleosides Nucleotides 1988, 7, 2, 147-53. |
| 【2】 Chu, C.K.; Bhadti, V.S.; Doboszewski, B.; Gu, Z.P.; Kosugi, Y.; Pullaiah, K.C.; Van Roey, P.; General syntheses of 2',3'-dideoxynucleosides and 2',3'-didehydro-2',3'-dideoxynucleosides. J Org Chem 1989, 54, 2217-25. |
| 【3】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 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) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 详情 | 详情 |
| (II) | 12796 | (2R,3S,4R,5R)-2-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol | C16H26N4O5Si | 详情 | 详情 | |
| (III) | 12797 | O-[(2R,3R,4R,5R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-([[(2-cyanoethyl)sulfanyl]carbothioyl]oxy)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3-furanyl] S-(2-cyanoethyl) carbonodithioate | C24H32N6O5S4Si | 详情 | 详情 | |
| (IV) | 12798 | 9-[(2R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C16H24N4O3Si | 详情 | 详情 | |
| (V) | 12799 | 9-[(2R,5S)-5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C10H10N4O3 | 详情 | 详情 | |
| (VI) | 12800 | (3aR,4R,6R,6aR)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-6-(6-hydroxy-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxole-2-thione | C17H24N4O5SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new synthesis of ddI has been described: The reaction of inosine (I) with 2-acetoxyisobutyryl bromide (II) gives a mixture of two bromodiacyloxy derivatives (IIIa) and (IIIb) that, without separation, are hydrolyzed either with ammonia in methanol or with the pair Zn-Cu in the same solvent, yielding a mixture of the 2- and 3-bromo derivatives (IVa) and (IVb). The acylation of this mixture with chlorothionoformic acid O-phenyl ester and dimethylaminopyridine (DMAP) in acetonitrile gives a new mixture of the thiono esters (Va) and (Vb), which is treated with tributyltin hydride and azoisobutyronitrile (AIBN) in refluxing benzene to yield 5'-O-(2-acetoxyisobutyryl)-2',3'-didehydro-2',3'-dideoxyinosine (VI). The hydrolysis of (VI) with ammonia in methanol affords 2',3'-didehydro-2',3'-dideoxyinosine (VII), which is finally hydrogenated with H2 over Pd/C.
| 【1】 Dorland, E.; Serafinowski, P.; A convenient method for the synthesis of 2',3'-dideoxynucleosides. Antivir Res 1992, 17, (Suppl. 1), Abst 26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 12807 | [(2R,3S,4S,5R)-4-(acetoxy)-3-bromo-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C18H21BrN4O8 | 详情 | 详情 | |
| (IIIb) | 12808 | [(2R,3R,4S,5R)-3-(acetoxy)-4-bromo-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C18H21BrN4O8 | 详情 | 详情 | |
| (IVa) | 12809 | [(2R,3R,4S,5R)-3-bromo-4-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H19BrN4O7 | 详情 | 详情 | |
| (IVb) | 12810 | [(2R,3R,4S,5R)-4-bromo-3-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H19BrN4O7 | 详情 | 详情 | |
| (Va) | 12811 | [(2R,3S,4S,5R)-3-bromo-5-(6-hydroxy-9H-purin-9-yl)-4-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C23H23BrN4O8S | 详情 | 详情 | |
| (Vb) | 12812 | [(2R,3R,4S,5R)-4-bromo-5-(6-hydroxy-9H-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C23H23BrN4O8S | 详情 | 详情 | |
| (I) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 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 |
| (VI) | 12813 | [(2S,5R)-5-(6-hydroxy-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H18N4O6 | 详情 | 详情 | |
| (VII) | 12799 | 9-[(2R,5S)-5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C10H10N4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Acylation of inosine (I) with Ac2O in the presence of pyridine yields inosine triacetate (II), which is then protected as the N-MEM derivative (III) using chloromethyl methyl ether and DIEA in CH2Cl2. Deacetylation of compound (III) with NH3 in MeOH affords 1-MEMinosine (IV), which finally undergoes purine ring opening in refluxing NaOH .
In a related method, acadesine is obtained by MEM protection of inosine acetate (II) with chloromethyl methyl ether by means of NaH in dioxane, and subsequent purine ring hydrolysis with NaOH in refluxing EtOH .
Similarly, direct hydrolysis of unprotected inosine (I) with KOH in water at 130 °C produces a mixture of acadesine and 9-β-D-ribopyranosylhypoxanthine, from which acadesine can be isolated using column chromatography .
An alternative strategy is the hydrolysis of the imidazolecarbonitrile (V) with NaOH at 100 °C .
In a different approach, reaction of 2’,3’-O-isopropylideneinosine (VI) with 2,4-dinitrochlorobenzene (DNCB) by means of K2CO3 at 80 °C yields N1-(2,4-dinitrophenyl)-2’,3’-O-isopropylideneinosine (VII), which is then O-deprotected with HCOOH in H2O to give 1-(2,4-dinitrophenyl) inosine (VIII). Regioselective attachment of the triol (VIII) to MMTCl resin in the presence of DMAP in pyridine provides the resin-bound compound (IX), which is then submitted to purine ring hydrolysis with EDA in DMF, and subsequent deprotection of the obtained intermediate with TFA in CH2Cl2 .
| 【1】 Kohyama, N., Yamamoto, Y. A facile synthesis of AICAR from inosine. Synthesis 2001, 17: 2639-42. |
| 【2】 Shaw, E. A chemical preparation of 5-amino-4-imidazolecarboxamide ribotide. J Am Chem Soc 1961, 83(23): 4770-2. |
| 【3】 Suzuki, Y. Action of alkali on inosine - Formation of 5-amino-1-beta-Dribofuranosyl-4-imidazolecarboxamide and 9-beta-D-ribopyranosyl hypoxanthine. Bull Chem Soc Jpn 1974, 47(4): 898-903. |
| 【4】 Ferris, J.P., Devadas, B., Huang, C.H., Ren, W.Y. Novel synthesis of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide and 5-amino-1-(beta-D-ribopyranosyl)imidazole-4-carboxamide. J Org Chem 1985, 50(6): 747-54. |
| 【5】 Oliviero, G., Amato, J., Borbone, N., D’Errico, S., Piccialli, G., Mayol, L. Synthesis of N-1 and ribose modified inosine analogues on solid support. Tetrahedron Lett 2007, 48(3): 397-400. |
| 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) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 详情 | 详情 |
| (II) | 38014 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (III) | 68809 | (2R,3R,4S,5R)-2-(acetoxymethyl)-5-(1-((2-methoxyethoxy)methyl)-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3,4-diyl diacetate | C20H26N4O10 | 详情 | 详情 | |
| (IV) | 68810 | 9-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1-((2-methoxyethoxy)methyl)-1H-purin-6(9H)-one | C14H20N4O7 | 详情 | 详情 | |
| (V) | 37430 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile | C9H12N4O4 | 详情 | 详情 | |
| (VI) | 68811 | 9-((3aS,4S,6S,6aS)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)-1H-purin-6(9H)-one | C13H16N4O5 | 详情 | 详情 | |
| (VII) | 68812 | 1-(2,4-dinitrophenyl)-9-((3aS,4S,6S,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-purin-6(9H)-one | C19H18N6O9 | 详情 | 详情 | |
| (VIII) | 68813 | 9-((2S,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1-(2,4-dinitrophenyl)-1H-purin-6(9H)-one | C16H14N6O9 | 详情 | 详情 | |
| (IX) | 68814 | C16H13N6O9 | 详情 | 详情 |