|
【结 构 式】 
|
【分子编号】12799 【品名】9-[(2R,5S)-5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol 【CA登记号】 |
【 分 子 式 】C10H10N4O3 【 分 子 量 】234.21456 【元素组成】C 51.28% H 4.3% N 23.92% O 20.49% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(VII)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 |