Dibenzyl diethylphosphoramidite

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (180 mg, 0.5 mmol) was dissolved in a mixture of 1H-tetrazole (350 mg, 5 mmol) in 10 ml of dry acetonitrile and 10 ml of dry methylene chloride. At room temperature dibenzyl diethylphosphoramidite (476 mg, 1.5 mmol) was added under nitrogen and the mixture was stirred for 2 h. Then 70% tert-butyl hydroperoxide solution (1 ml) was added and the mixture was stirred for 1 h. At 0° C. 15 ml of 10% NaHSO3 was added and the mixture was stirred for another 15 minutes. The mixture was then extracted three times with CH2Cl2, and the organic layer was washed water. Evaporation of solvent yielded Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester as a yellow oil, which was purified by column chromatography. Fractions contained Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester was combined and concentrated in vacuum to get 280 mg product. MS (M+1) 621. the mixture was stirred for 1 h At 0° C the mixture was stirred for another 15 minutes The mixture was then extracted three times with CH2Cl2 the organic layer was washed water Evaporation of solvent

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with 50% ethyl acetate in chloroform and ending with ethyl acetate, to give the title compound (0.922 g, 45%). the mixture was cooled to −45° C. The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour the reaction was extracted twice with chloroform The combined organic layer was dried over MgSO4 filtered evaporated The residue was purified by chromatography on silica gel eluting with a gradient

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform, to give the title compound (0.396 g, 17%). the mixture was cooled to −45° C. The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour the reaction was extracted twice with chloroform The combined organic layer was dried over MgSO4 filtered evaporated The residue was purified by chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in chloroform

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform, to give the title compound (0.396 g, 17%). the mixture was cooled to −45° C. The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour the reaction was extracted twice with chloroform The combined organic layer was dried over MgSO4 filtered evaporated The residue was purified by chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in chloroform

Conditions: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of the compound of Example 1 (6.0 g, 8.32 mmol), dibenzyl diethylphosphoramidite (3.96 g), and 1H-tetrazole (2.63 g) in THF (100 mL) was stirred at room temperature for 4 hours. The mixture was cooled to −45° C., followed by dropwise addition of a solution of m-chloroperbenzoic acid (7.2 g) in dichloromethane (100 mL). The mixture was warmed to room temperature and stirred for 1 hour. A 10% solution of Na2S2O3 (100 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate and washed with 10% Na2S2O3 and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 2% methanol in dichloromethane containing 0.05% NH4OH, to give the title compound (6.2 g, 76% yield). The mixture was warmed to room temperature the mixture was stirred for 30 minutes The reaction mixture was extracted with ethyl acetate washed with 10% Na2S2O3 and saturated NaHCO3 The organic phase was dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel eluting with 2% methanol in dichloromethane containing 0.05% NH4OH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform, to give the title compound (0.396 g, 17%). the mixture was cooled to −45° C. The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour the reaction was extracted twice with chloroform The combined organic layer was dried over MgSO4 filtered evaporated The residue was purified by chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in chloroform

Conditions: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of the compound of Example 1 (6.0 g, 8.32 mmol), dibenzyl diethylphosphoramidite (3.96 g), and 1H-tetrazole (2.63 g) in THF (100 mL) was stirred at room temperature for 4 hours. The mixture was cooled to −45° C., followed by dropwise addition of a solution of m-chloroperbenzoic acid (7.2 g) in dichloromethane (100 mL). The mixture was warmed to room temperature and stirred for 1 hour. A 10% solution of Na2S2O3 (100 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate and washed with 10% Na2S2O3 and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 2% methanol in dichloromethane containing 0.05% NH4OH, to give the title compound (6.2 g, 76% yield). The mixture was warmed to room temperature the mixture was stirred for 30 minutes The reaction mixture was extracted with ethyl acetate washed with 10% Na2S2O3 and saturated NaHCO3 The organic phase was dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel eluting with 2% methanol in dichloromethane containing 0.05% NH4OH

Conditions: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of the compound of Example 3 (0.250 g, 0.40 mmol), dibenzyl diethylphosphoramidite (0.28 mL), and 1H-tetrazole (0.14 g) in THF (4.0 mL) was stirred at room temperature for 68 hours. Dichloromethane (4.0 mL) was added and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (0.089 g). After stirring for 30 minutes at −45° C., the reaction was diluted with ethyl acetate and washed twice with 10% Na2CO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatography on silica gel, eluting with a gradient starting with 33% ethyl acetate in chloroform and ending with 5% methanol in ethyl acetate, to give the title compound (0.324 g, 90% yield). washed twice with 10% Na2CO3 The organic phase was dried over MgSO4 filtered evaporated eluting with a gradient