magnesium;2-methylpropan-2-olate

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

Procedure: Accordingly (R)-9-[2-(hydroxyl)propyl]adenine is condensed with Diethyl p-toluene sulfonyloxy methylphosphonate in presence of Magnesium tert-butoxide in a polar solvent preferably dimethylformamide at a temperature of 70° C. to 80° C. After the reaction completion the reaction mass is neutralized by adding an acid preferably acetic acid and the solvent is distilled off completely. The obtained crude is dissolved in a chlorinated hydrocarbon selected from Methylenedichloride, chloroform, and Ethylene dichloride and water is added. The reaction mixture is filtered to remove the salts and Methylenedichloride layer is separated. Methylenedichloride is distilled off completely to get (R)-9-[2-(phosphonomethoxy)propyl]adenine. the solvent is distilled off completely The obtained crude is added The reaction mixture is filtered to remove the salts and Methylenedichloride layer is separated Methylenedichloride is distilled off completely

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adenine to PMPA using Magnesium t-Butoxide. To a suspension of adenine (40 g, 0.296 mol) in DMF (41.9 ml) was added (R)-propylene carbonate (34.5 g, 0.338 mol) and sodium hydroxide (0.480 g, 0.012 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to 100° C. and toluene (138 ml) was added followed by methanesulfonic acid (4.7 g, 0.049 mol) while maintaining the reaction temperature between 100-110° C. Additional toluene (114 ml) was added to create a homogeneous solution. The solution was cooled to 3° C. over 7 hours and then held at 3° C. for one hour. The resulting solid was isolated by filtration and rinsed with acetone (2×). The wet solid was dried in vacuo at 80° C. to yield 42.6 g (75%) of (R)-9-[2-(hydroxy)propyl]adenine (HPA) as an off-white solid. Mp: 188-190° C. The reaction was cooled to 100° C. while maintaining the reaction temperature between 100-110° C The solution was cooled to 3° C. over 7 hours The resulting solid was isolated by filtration rinsed with acetone (2×) The wet solid was dried in vacuo at 80° C.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-(2-Hydroxyethyl)adenine (HEA) (20.0 g, 0.112 mol) was suspended in DMF (125 ml) and heated to 80° C. Magnesium isopropoxide (11.2 g, 0.0784 mol), or alternatively magnesium t-butoxide, was added to the mixture followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.162 mol) over one hour. The mixture was stirred at 80° C. for 7 hours. 30 ml of volatiles were removed via vacuum distillation and the reaction was recharged with 30 ml of fresh DMF. After cooling to room temperature, bromotrimethylsilane (69.6 g, 0.450 mol) was added and the mixture heated to 80° C. for 6 hours. The reaction was concentrated to yield a thick gum. The gum was dissolved into 360 ml water, extracted with 120 ml dichloromethane, adjusted to pH 3.2 with sodium hydroxide, and the resulting slurry stirred at room temperature overnight. The slurry was cooled to 4° C. for one hour. The solids were isolated by filtration, washed with water (2×), and dried in vacuo at 56° C. to yield 20 g (65.4%) of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as a white solid. Mp:>200° C. dec. 1H NMR (D2O) δ 3.49 (t, 2H); 3.94 (t, 2H); 4.39 (t, 2H); 8.13 (s, 1H); 8.22 (s, 1H). 30 ml of volatiles were removed via vacuum distillation After cooling to room temperature the mixture heated to 80° C. for 6 hours The reaction was concentrated to yield a thick gum extracted with 120 ml dichloromethane the resulting slurry stirred at room temperature overnight The slurry was cooled to 4° C. for one hour The solids were isolated by filtration washed with water (2×) dried in vacuo at 56° C.

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

Procedure: 140 mg (purity 87%, 0.37 mmol) of 4-chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. and, after aqueous work-up, used without purification for the next step. Yield: 214 mg (purity 73%, quant.) according to General Method 4A at 50° C. after aqueous work-up, used without purification for the next step

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

Procedure: 163 mg (0.55 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted at 45° C. and worked up according to General Method 4A. Owing to incomplete conversion, the crude product was then once more reacted as described above with 1.2 eq. of magnesium di-tert-butoxide, 0.65 eq. of potassium tert-butoxide and 0.8 eq. of 2-bromopropionic acid (racemate) in 3.5 ml of tetrahydrofuran and worked up analogously. Yield: 270 mg (purity 63%, 84% of theory)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adenine to PMPA using Magnesium t-Butoxide. To a suspension of adenine (40 g, 0.296 mol) in DMF (41.9 ml) was added (R)-propylene carbonate (34.5 g, 0.338 mol) and sodium hydroxide (0.480 g, 0.012 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to 100° C. and toluene (138 ml) was added followed by methanesulfonic acid (4.7 g, 0.049 mol) while maintaining the reaction temperature between 100-110° C. Additional toluene (114 ml) was added to create a homogeneous solution. The solution was cooled to 3° C. over 7 hours and then held at 3° C. for one hour. The resulting solid was isolated by filtration and rinsed with acetone (2×). The wet solid was dried in vacuo at 80° C. to yield 42.6 g (75%) of (R)-9-[2-(hydroxy)propyl]adenine (HPA) as an off-white solid. Mp: 188-190° C. The reaction was cooled to 100° C. while maintaining the reaction temperature between 100-110° C The solution was cooled to 3° C. over 7 hours The resulting solid was isolated by filtration rinsed with acetone (2×) The wet solid was dried in vacuo at 80° C.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-(2-Hydroxyethyl)adenine (HEA) (20.0 g, 0.112 mol) was suspended in DMF (125 ml) and heated to 80° C. Magnesium isopropoxide (11.2 g, 0.0784 mol), or alternatively magnesium t-butoxide, was added to the mixture followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.162 mol) over one hour. The mixture was stirred at 80° C. for 7 hours. 30 ml of volatiles were removed via vacuum distillation and the reaction was recharged with 30 ml of fresh DMF. After cooling to room temperature, bromotrimethylsilane (69.6 g, 0.450 mol) was added and the mixture heated to 80° C. for 6 hours. The reaction was concentrated to yield a thick gum. The gum was dissolved into 360 ml water, extracted with 120 ml dichloromethane, adjusted to pH 3.2 with sodium hydroxide, and the resulting slurry stirred at room temperature overnight. The slurry was cooled to 4° C. for one hour. The solids were isolated by filtration, washed with water (2×), and dried in vacuo at 56° C. to yield 20 g (65.4%) of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as a white solid. Mp:>200° C. dec. 1H NMR (D2O) δ 3.49 (t, 2H); 3.94 (t, 2H); 4.39 (t, 2H); 8.13 (s, 1H); 8.22 (s, 1H). 30 ml of volatiles were removed via vacuum distillation After cooling to room temperature the mixture heated to 80° C. for 6 hours The reaction was concentrated to yield a thick gum extracted with 120 ml dichloromethane the resulting slurry stirred at room temperature overnight The slurry was cooled to 4° C. for one hour The solids were isolated by filtration washed with water (2×) dried in vacuo at 56° C.

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

Procedure: 140 mg (purity 87%, 0.37 mmol) of 4-chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. and, after aqueous work-up, used without purification for the next step. Yield: 214 mg (purity 73%, quant.) according to General Method 4A at 50° C. after aqueous work-up, used without purification for the next step

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

Procedure: 163 mg (0.55 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted at 45° C. and worked up according to General Method 4A. Owing to incomplete conversion, the crude product was then once more reacted as described above with 1.2 eq. of magnesium di-tert-butoxide, 0.65 eq. of potassium tert-butoxide and 0.8 eq. of 2-bromopropionic acid (racemate) in 3.5 ml of tetrahydrofuran and worked up analogously. Yield: 270 mg (purity 63%, 84% of theory)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-(tert-Butyl-diphenyl-silanyloxymethyl)-but-2-en-1-ol (see: J. Org. Chem. 58, 2151-2161, 1993), (660 mg (1.94 mmol)) in anhydrous DMF was added Magnesium t-butoxide 660 mg (3.88 mmol) followed by isopropylphosphonate tosylate 1.2 g (2.91 mmol). The reaction was stirred under Ar at 70° C. for 16 h, until the reaction was complete by TLC. Solvents were removed in vacuo and the residue (yellow gum) resuspended in EtOAc. Saturated NH4Cl— was added and the reaction extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (gradient elution, hexanes/ethyl acetate, 9:1 to 2:3) yielded the title compound 674 mg (1.3 mmol; 67% yield). Solvents were removed in vacuo Saturated NH4Cl— was added the reaction extracted with EtOAc (2×40 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo Flash chromatography (gradient elution, hexanes/ethyl acetate, 9:1 to 2:3)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-9-[2-(hydroxy)propyl]adenine (HPA) (20.0 g, 0.104 mol) was suspended in DMF (44.5 ml) and heated to 65° C. Magnesium t-butoxide (14.2 g, 0.083 mol), or alternatively magnesium isopropoxide, was added to the mixture over one hour followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.205 mol) over two hours while the temperature was kept at 78° C. The mixture was stirred at 75° C. for 4 hours. After cooling to below 50° C., bromotrimethylsilane (73.9 g, 0.478 mol) was added and the mixture heated to 77° C. for 3 hours. When complete, the reaction was heated to 80° C. and volatiles were removed via atmospheric distillation. The residue was dissolved into water (120 ml) at 50° C. and then extracted with ethyl acetate (101 ml). The pH of the aqueous phase was adjusted to pH 1.1 with sodium hydroxide, seeded with authentic (R)-PMPA, and the pH of the aqueous layer was readjusted to pH 2.1 with sodium hydroxide. The resulting slurry was stirred at room temperature overnight. The slurry was cooled to 4° C. for three hours. The solid was isolated by filtration, washed with water (60 ml), and dried in vacuo at 50° C. to yield 18.9 g (63.5%) of crude (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) as an off-white solid. was kept at 78° C After cooling to below 50° C. the mixture heated to 77° C. for 3 hours When complete, the reaction was heated to 80° C. volatiles were removed via atmospheric distillation The residue was dissolved into water (120 ml) at 50° C. extracted with ethyl acetate (101 ml) The resulting slurry was stirred at room temperature overnight The slurry was cooled to 4° C. for three hours The solid was isolated by filtration washed with water (60 ml) dried in vacuo at 50° C.

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adenine to PMPA using Magnesium t-Butoxide. To a suspension of adenine (40 g, 0.296 mol) in DMF (41.9 ml) was added (R)-propylene carbonate (34.5 g, 0.338 mol) and sodium hydroxide (0.480 g, 0.012 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to 100° C. and toluene (138 ml) was added followed by methanesulfonic acid (4.7 g, 0.049 mol) while maintaining the reaction temperature between 100-110° C. Additional toluene (114 ml) was added to create a homogeneous solution. The solution was cooled to 3° C. over 7 hours and then held at 3° C. for one hour. The resulting solid was isolated by filtration and rinsed with acetone (2×). The wet solid was dried in vacuo at 80° C. to yield 42.6 g (75%) of (R)-9-[2-(hydroxy)propyl]adenine (HPA) as an off-white solid. Mp: 188-190° C. The reaction was cooled to 100° C. while maintaining the reaction temperature between 100-110° C The solution was cooled to 3° C. over 7 hours The resulting solid was isolated by filtration rinsed with acetone (2×) The wet solid was dried in vacuo at 80° C.