9-[2,3,5-TRI-O-ACETYL-BETA-D-RIBOFURANOSYL]-2,6-DICHLOROPURINE

Off-White to Pale Yellow Solid

Isoamyl nitrite (165 g, 1.41 mol) was dissolved in methylene chloride (500 mL) and then stirred at 0~5 ° C.Trimethylchlorosilane (76 g, 0.70 mol) was added, Then a solution of compound IV (100 g, 0.234 mol) in DCM was added(500mL) was added dropwise to the above mother liquor, after the addition was complete, Continue to stir the reaction at this temperature for 1 hour, The reaction was completed, saturated sodium sulfite solution, liquid separation, The separated organic phase was washed with aqueous sodium bicarbonate, Washed with saturated saline, and dried over anhydrous sodium sulfate, filtered, The mixture was concentrated under reduced pressure until no solution was distilled off. The residue was recrystallized by adding dichloromethane (100 mL) and n-heptane (350 mL)The resulting yellow solid, Compound V (2, 6-dichloro-9- (2 ', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl) purine) 86g, molar yield of 82percent.2, 6-Dichloropurine (23) (190 mg, 1 mmol) and 1, 2, 3, 5-tetra-O-acetyl-β-D-ribofuranose (318 mg, 1 mmol) were dissolved in EtOAc, then 500 mg of silica gel 60 (200-400 mesh) was added. The mixture was concentrated in vacuo and the dry residue was irradiated for 30 min in a domestic microwave oven (120 W). The residue was purified by flash chromatography on silica gel (EtOAc-hexane, 1:2) to yield 24 as yellowish viscous oil (350 mg, 79percent). 2, 6-Dichloropurine (23) (190 mg, 1 mmol) and 1, 2, 3, 5-tetra-O-acetyl-beta-D-ribofuranose (318 mg, 1 mmol) were dissolved in EtOAc, then 500 mg of silica gel 60 (200-400 mesh) was added. The mixture was concentrated in vacuo and the dry residue was irradiated for 30 min in a domestic microwave oven (120 W). The residue was purified by flash chromatography on silica gel (EtOAc-hexane, 1:2) to yield 24 as yellowish viscous oil (350 mg, 79%). 1H NMR (CDCl3) delta2.10 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.17 (s, 3H, CH3), 4.42 (d, 2H, CH2-5?), 4.50 (q, 1H, H-4?), 5.59 (t, 1H, H-3?), 5.81 (t, 1H, H-2?), 6.24 (d, 1H, H-1?), 8.33 (s, 1H, H-8). 13C NMR (DMSO-d6) delta 20.53, 20.70, 20.95 (3xCH3), 63.06 (CH2-5?), 70.72 (CH-4?), 73.42 (CH-3?), 81.02 (CH-2?), 86.74 (CH-1?), 131.56 (C-5), 144.10 (C-8), 152.44 (C-6), 152.79 (C-4), 153.55 (C-2), 169.56, 169.74, 170.39 (3xCO). MS (ESI+) m/e: 447.5 (%100) (M), 449.9 (%50) (M+2), 451.6 (%17) (M+4).First, 21 g of ribofuranose tetraacetate (6) was heated to 90 C untilit became clear, and 12 g of 2, 6-dichloropurine (7) and 0.3 g ofstannic chloride were added with stirring. The reactionwas furtherheated and stirred at 120 C for 15 min. The solvent was evaporatedunder a vacuum, and the residue was cooled. Methanol (50 ml) wasadded to the residue, and the solid isolated by filtration yielded thecrude product. The crude product was recrystallized from ethanolto yield 12 g of 2, 6-dichloro-9-(2', 3', 5'-tri-O-acetyl-beta-D-ribofuranosyl)purine.Preparation 1 2-Chloro-N-(2, 2-diphenylethyl)-adenosine 2', 3', 5'-triacetate A solution of 2, 6-dichloro-9-(2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine1 (6.68 g, 14.9 mmol) in 2-propanol (300 ml) was stirred and heated at reflux with 2, 2-diphenylethylamine (4.3 g, 21.8 mmol) in the presence of diisopropylethylamine (3.8 ml) for 3.5 h. The cooled mixture was reduced in volume by evaporation in vacuo and the residue was diluted with ethyl acetate (200 ml). This mixture was washed with water (100 ml); 10% citric acid solution (2*100 ml) and water (100 ml) then dried (MgSO4) and evaporated to give the title compound (9.01 g) as a pale yellow froth. A sample (500 mg) was purified by column chromatography on flash silica eluding with ethyl acetate:cyclohexane (1:2). The product (0.34 g) was obtained as a white froth [alpha]D -20 (CHCl3 c=1%).

Protected nucleoside.