[3-acetyloxy-2-(acetyloxymethoxy)propyl] acetate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Nitroimidazole was subjected to trimethylsilylation by use of hexamethyldisilazane in acetonitrile, and the resultant compound and 2-acetoxymethoxy-1,3-diacetoxypropane were subjected to condensation by use of stannic chloride serving as a catalyst. The resultant product was deprotected by use of methanolic ammonia, to thereby obtain 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole. The thus-obtained 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (0.5 g) was refluxed for two hours together with dibutyl tin oxide (0.6 g) in anhydrous toluene in the presence of molecular sieves having a pore size of 4 Å. The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue. The resultant mixture was cooled to 0° C., and acetyl chloride (171 mg) was added to the mixture, and then the mixture was stirred for 30 minutes. To the resultant reaction mixture, a sodium phosphate buffer having a pH of 7.1 (10 mL) was added, and the resultant mixture was subjected to filtration. The resultant residue was subjected to extraction with chloroform (10 mL×3), and the thus-obtained extract was mixed with the filtrate, and the mixture was separated, thereby obtaining an organic layer. The organic layer was dried over sodium sulfate, and then fractionated and purified through silica gel chromatography, to thereby yield the title compound, 1-[1-acetoxymethyl-2-(hydroxy)ethoxy]methyl-2-nitroimidazole (265 mg). The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue acetyl chloride (171 mg) was added to the mixture To the resultant reaction mixture was added the resultant mixture was subjected to filtration The resultant residue was subjected to extraction with chloroform (10 mL×3) the thus-obtained extract was mixed with the filtrate the mixture was separated obtaining an organic layer The organic layer was dried over sodium sulfate purified through silica gel chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2.33 g (9.4 mmoles) of acetoxymethyl 1,3-diacetoxy-2-propyl ether in 22 ml of sieve-dried methylene chloride was stirred at room temperature while a slow stream of anhydrous hydrogen chloride was passed through the solution. Anhydrous conditions were maintained throughout the reaction. After two hours the reaction was judged to be complete by nuclear magnetic resonance spectroscopy. The reaction mixture was purged with nitrogen and concentrated in vacuo. The residue was taken up in a small volume of toluene and concentrated in vacuo. This was repeated twice and then the residue was pumped in vacuo to remove residual solvent. The yield of chloromethyl 1,3-diacetoxy-2-propyl ether is 1.92 g (91%). Anhydrous conditions were maintained throughout the reaction The reaction mixture was purged with nitrogen concentrated in vacuo concentrated in vacuo to remove residual solvent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round-bottomed flask (10 ml) was charged with N-acetyl-2-acetamido-6-chloropurine (2.0 g, 7.9 mmoles), 1,3-diacetoxy-2-propoxymethyl acetate (2.7 g, 10.9 mmoles), and ethanesulfonic acid (63 mg). The mixture was heated in an oil bath maintained at 130° and a vacuum was applied. Thin layer chromatography showed no heterocyclic starting material after 1.5 hours and heating was discontinued. The mixture was dissolved in dichloromethane (50 ml) and filtered through Celite. The filtrate was evaporated to a residue and chromatographed on silica gel using dichloromethane/methanol (98:2) as the eluant. The product-containing fractions were combined and evaporated to give 0.75 g of pure product, m.p. 139°-140°. The mixture was heated in an oil bath maintained at 130° after 1.5 hours heating filtered through Celite The filtrate was evaporated to a residue chromatographed on silica gel evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%). connected with a trap The flask was heated by oil bath of 130°-140° C. under reduced pressure Acetic acid was distilled out as the reaction the content was added with about 300 ml ethyl acetate subjected to extraction The extract was washed with saturated aqueous sodium hydrogen carbonate Then it was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by separable high performance liquid chromatography through silica gel columns

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%). connected with a trap The flask was heated by oil bath of 130°-140° C. under reduced pressure Acetic acid was distilled out as the reaction the content was added with about 300 ml ethyl acetate subjected to extraction The extract was washed with saturated aqueous sodium hydrogen carbonate Then it was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by separable high performance liquid chromatography through silica gel columns

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Nitroimidazole was subjected to trimethylsilylation by use of hexamethyldisilazane in acetonitrile, and the resultant compound and 2-acetoxymethoxy-1,3-diacetoxypropane were subjected to condensation by use of stannic chloride serving as a catalyst. The resultant product was deprotected by use of methanolic ammonia, to thereby obtain 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole. The thus-obtained 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (0.5 g) was refluxed for two hours together with dibutyl tin oxide (0.6 g) in anhydrous toluene in the presence of molecular sieves having a pore size of 4 Å. The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue. The resultant mixture was cooled to 0° C., and acetyl chloride (171 mg) was added to the mixture, and then the mixture was stirred for 30 minutes. To the resultant reaction mixture, a sodium phosphate buffer having a pH of 7.1 (10 mL) was added, and the resultant mixture was subjected to filtration. The resultant residue was subjected to extraction with chloroform (10 mL×3), and the thus-obtained extract was mixed with the filtrate, and the mixture was separated, thereby obtaining an organic layer. The organic layer was dried over sodium sulfate, and then fractionated and purified through silica gel chromatography, to thereby yield the title compound, 1-[1-acetoxymethyl-2-(hydroxy)ethoxy]methyl-2-nitroimidazole (265 mg). The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue acetyl chloride (171 mg) was added to the mixture To the resultant reaction mixture was added the resultant mixture was subjected to filtration The resultant residue was subjected to extraction with chloroform (10 mL×3) the thus-obtained extract was mixed with the filtrate the mixture was separated obtaining an organic layer The organic layer was dried over sodium sulfate purified through silica gel chromatography

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Nitroimidazole was subjected to trimethylsilylation by use of hexamethyldisilazane in acetonitrile, and the resultant compound and 2-acetoxymethoxy-1,3-diacetoxypropane were subjected to condensation by use of stannic chloride serving as a catalyst. The resultant product was deprotected by use of methanolic ammonia, to thereby obtain 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole. The thus-obtained 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (0.5 g) was refluxed for two hours together with dibutyl tin oxide (0.6 g) in anhydrous toluene in the presence of molecular sieves having a pore size of 4 Å. The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue. The resultant mixture was cooled to 0° C., and acetyl chloride (171 mg) was added to the mixture, and then the mixture was stirred for 30 minutes. To the resultant reaction mixture, a sodium phosphate buffer having a pH of 7.1 (10 mL) was added, and the resultant mixture was subjected to filtration. The resultant residue was subjected to extraction with chloroform (10 mL×3), and the thus-obtained extract was mixed with the filtrate, and the mixture was separated, thereby obtaining an organic layer. The organic layer was dried over sodium sulfate, and then fractionated and purified through silica gel chromatography, to thereby yield the title compound, 1-[1-acetoxymethyl-2-(hydroxy)ethoxy]methyl-2-nitroimidazole (265 mg). The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue acetyl chloride (171 mg) was added to the mixture To the resultant reaction mixture was added the resultant mixture was subjected to filtration The resultant residue was subjected to extraction with chloroform (10 mL×3) the thus-obtained extract was mixed with the filtrate the mixture was separated obtaining an organic layer The organic layer was dried over sodium sulfate purified through silica gel chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2.33 g (9.4 mmoles) of acetoxymethyl 1,3-diacetoxy-2-propyl ether in 22 ml of sieve-dried methylene chloride was stirred at room temperature while a slow stream of anhydrous hydrogen chloride was passed through the solution. Anhydrous conditions were maintained throughout the reaction. After two hours the reaction was judged to be complete by nuclear magnetic resonance spectroscopy. The reaction mixture was purged with nitrogen and concentrated in vacuo. The residue was taken up in a small volume of toluene and concentrated in vacuo. This was repeated twice and then the residue was pumped in vacuo to remove residual solvent. The yield of chloromethyl 1,3-diacetoxy-2-propyl ether is 1.92 g (91%). Anhydrous conditions were maintained throughout the reaction The reaction mixture was purged with nitrogen concentrated in vacuo concentrated in vacuo to remove residual solvent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round-bottomed flask (10 ml) was charged with N-acetyl-2-acetamido-6-chloropurine (2.0 g, 7.9 mmoles), 1,3-diacetoxy-2-propoxymethyl acetate (2.7 g, 10.9 mmoles), and ethanesulfonic acid (63 mg). The mixture was heated in an oil bath maintained at 130° and a vacuum was applied. Thin layer chromatography showed no heterocyclic starting material after 1.5 hours and heating was discontinued. The mixture was dissolved in dichloromethane (50 ml) and filtered through Celite. The filtrate was evaporated to a residue and chromatographed on silica gel using dichloromethane/methanol (98:2) as the eluant. The product-containing fractions were combined and evaporated to give 0.75 g of pure product, m.p. 139°-140°. The mixture was heated in an oil bath maintained at 130° after 1.5 hours heating filtered through Celite The filtrate was evaporated to a residue chromatographed on silica gel evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round-bottomed flask (10 ml) was charged with N-acetyl-2-acetamido-6-chloropurine (2.0 g, 7.9 mmoles), 1,3-diacetoxy-2-propoxymethyl acetate (2.7 g, 10.9 mmoles), and ethanesulfonic acid (63 mg). The mixture was heated in an oil bath maintained at 130° and a vacuum was applied. Thin layer chromatography showed no heterocyclic starting material after 1.5 hours and heating was discontinued. The mixture was dissolved in dichloromethane (50 ml) and filtered through Celite. The filtrate was evaporated to a residue and chromatographed on silica gel using dichloromethane/methanol (98:2) as the eluant. The product-containing fractions were combined and evaporated to give 0.75 g of pure product, m.p. 139°-140°. The mixture was heated in an oil bath maintained at 130° after 1.5 hours heating filtered through Celite The filtrate was evaporated to a residue chromatographed on silica gel evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%). connected with a trap The flask was heated by oil bath of 130°-140° C. under reduced pressure Acetic acid was distilled out as the reaction the content was added with about 300 ml ethyl acetate subjected to extraction The extract was washed with saturated aqueous sodium hydrogen carbonate Then it was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by separable high performance liquid chromatography through silica gel columns

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 50.0 g (0.33 mole) of guanine, 33 g of ammonium sulfate, and 2.2 l of hexamethyldisilazane was stirred at reflux under N2 for 3 days, during which time all of the solid dissolved. The solvent was then removed by distillation under reduced pressure. To the very viscous, orange residual oil was added under N2 84 g (0.34 mole) of acetoxymethyl 1,3-diacetoxy-2-propyl ether, which formed in second liquid phase at the bottom of the flask. The flask was fitted with a distillation adapter, and the mixture was heated under low vacuum in an oil bath at approximately 135°. After an induction period lasting several minutes, boiling began and soon became quite vigorous. Distillation of trimethylsilyl acetate (along with any residual hexamethyldisilazane) proceeded rapidly at first but slowed after 30 minutes. After 2 hours the mixture was added to 1.3 l of 90% EtOH. The mixture was heated to boiling and maintained there until the separated gummy material was transformed to a tractable solid. The solid (8.2 g, consisting almost exclusively of guanine) was removed by filtration while hot. The filtrate was allowed to stand overnight, resulting in separation of an orange-brown gum. The supernatant was decanted away from the gum, filtered, and then concentrated to small volume. The solid which separated on concentration was collected on a filter and washed with H2O, then with some EtOH, to give 15.4 g of cream-colored crystals. By NMR, this material was solely the -alkylated isomer, although TLC indicated partial side chain deactylation. The material was suitable for deprotection without further purification. at reflux under N2 for 3 days, during which time all of the solid dissolved The solvent was then removed by distillation under reduced pressure formed in second liquid phase at the bottom of the flask The flask was fitted with a distillation adapter the mixture was heated under low vacuum in an oil bath at approximately 135° After an induction period lasting several minutes Distillation of trimethylsilyl acetate (along with any residual hexamethyldisilazane) After 2 hours the mixture was added to 1.3 l of 90% EtOH The mixture was heated maintained there until the separated gummy material was removed by filtration while hot to stand overnight resulting in separation of an orange-brown gum The supernatant was decanted away from the gum filtered concentrated to small volume The solid which separated on concentration was collected on a filter washed with H2O