diethyl phosphate

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:

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

Procedure: To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added adenine (4.7 g, 34.5 mmol) and the mixture was stirred at 80° C. for 1 hr. To the resulting yellow solution was added dropwise a solution of chloromethoxy-(diethoxyphosphinomethoxy)methane [(prepared from diethylphosphate (4.4 mL, 34.5 mmol) and bis-(chloromethoxy)methane (25 g, 172 mmol)] in DMF (20 mL) under nitrogen. After stirring at 25° C. for 15 hr, volatiles were removed in vacuo, and the resulting oily residue was purified by silica gel column chromatography using CH2Cl2 /10% MeOH as eluent to obtain the title compound as a colorless oil: yield 6.0 g (50%). After stirring at 25° C. for 15 hr volatiles were removed in vacuo the resulting oily residue was purified by silica gel column chromatography

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: A mixture of 2-amino-5-bromopyridine (5 g, 0.029 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.), diethyl phosphate (5.02 g, 0.036 mol), triethylamine (4.4 g, 0.043 mol), Pd(OAc)2 (0.78 g, 3.4 mmol), triphenylphosphine (2.28 g, 8.7 mmol) in ethanol (100 mL) was refluxed for 14 hours under nitrogen. TLC (Petroleum ether/ethyl acetate=1:1) indicated that the reaction was complete. The resulting mixture was filtered, and the filtrate was concentrated in vacuo, the residue was purified by prep. HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid; m/z 231.3 (M+H)+. was refluxed for 14 hours under nitrogen The resulting mixture was filtered the filtrate was concentrated in vacuo the residue was purified by prep HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid

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

Procedure: A mixture of 2-amino-5-bromopyridine (5 g, 0.029 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.), diethyl phosphate (5.02 g, 0.036 mol), triethylamine (4.4 g, 0.043 mol), Pd(OAc)2 (0.78 g, 3.4 mmol), triphenylphosphine (2.28 g, 8.7 mmol) in ethanol (100 mL) was refluxed for 14 hours under nitrogen. TLC (Petroleum ether/ethyl acetate=1:1) indicated that the reaction was complete. The resulting mixture was filtered, and the filtrate was concentrated in vacuo, the residue was purified by prep. HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid; m/z 231.3 (M+H)+. was refluxed for 14 hours under nitrogen The resulting mixture was filtered the filtrate was concentrated in vacuo the residue was purified by prep HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid

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

Procedure: To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 18, 4.674 g, 23.35 mmol) in 1,2-dichloroethane (70 mL) were added N-bromosuccinimide (4.57 g, 25.68 mmol) and benzoyl peroxide (56 mg, 0.23 mmol) and the mixture was heated to 70° C. for 2 days. The reaction mixture was allowed to cool, quenched with saturated aqueous sodium thiosulfate (20 mL) and diluted with water (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×80 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate, followed by brine, then filtered through a phase separator and concentrated in vacuo. The resulting yellow oil was redissolved in EtOAc (70 mL), and N,N-diisopropylethylamine (4.04 mL, 23.35 mmol) was added. The mixture was cooled to 0° C., and diethyl phosphate (2.29 mL, 23.35 mmol) was added. After stirring at 0° C. for 90 minutes, LCMS indicated complete conversion of the dibromomethyl impurity to the desired mono-bromomethyl product. The reaction was quenched at 0° C. with water (70 mL), followed by aqueous hydrochloric acid (2N, 10 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane to afford the title compound as a clear oil (5.78 g, 89%): to cool quenched with saturated aqueous sodium thiosulfate (20 mL) diluted with water (50 mL) The organic layer was separated the aqueous layer extracted with DCM (2×80 mL) The combined organics were washed with saturated aqueous sodium hydrogen carbonate filtered through a phase separator concentrated in vacuo The resulting yellow oil was redissolved in EtOAc (70 mL) The mixture was cooled to 0° C. The reaction was quenched at 0° C. with water (70 mL) The organic layer was separated washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo to yield a yellow residue The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane

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

Procedure: To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 18, 4.674 g, 23.35 mmol) in 1,2-dichloroethane (70 mL) were added N-bromosuccinimide (4.57 g, 25.68 mmol) and benzoyl peroxide (56 mg, 0.23 mmol) and the mixture was heated to 70° C. for 2 days. The reaction mixture was allowed to cool, quenched with saturated aqueous sodium thiosulfate (20 mL) and diluted with water (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×80 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate, followed by brine, then filtered through a phase separator and concentrated in vacuo. The resulting yellow oil was redissolved in EtOAc (70 mL), and N,N-diisopropylethylamine (4.04 mL, 23.35 mmol) was added. The mixture was cooled to 0° C., and diethyl phosphate (2.29 mL, 23.35 mmol) was added. After stirring at 0° C. for 90 minutes, LCMS indicated complete conversion of the dibromomethyl impurity to the desired mono-bromomethyl product. The reaction was quenched at 0° C. with water (70 mL), followed by aqueous hydrochloric acid (2N, 10 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane to afford the title compound as a clear oil (5.78 g, 89%): to cool quenched with saturated aqueous sodium thiosulfate (20 mL) diluted with water (50 mL) The organic layer was separated the aqueous layer extracted with DCM (2×80 mL) The combined organics were washed with saturated aqueous sodium hydrogen carbonate filtered through a phase separator concentrated in vacuo The resulting yellow oil was redissolved in EtOAc (70 mL) The mixture was cooled to 0° C. The reaction was quenched at 0° C. with water (70 mL) The organic layer was separated washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo to yield a yellow residue The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane

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

Procedure: To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added adenine (4.7 g, 34.5 mmol) and the mixture was stirred at 80° C. for 1 hr. To the resulting yellow solution was added dropwise a solution of chloromethoxy-(diethoxyphosphinomethoxy)methane [(prepared from diethylphosphate (4.4 mL, 34.5 mmol) and bis-(chloromethoxy)methane (25 g, 172 mmol)] in DMF (20 mL) under nitrogen. After stirring at 25° C. for 15 hr, volatiles were removed in vacuo, and the resulting oily residue was purified by silica gel column chromatography using CH2Cl2 /10% MeOH as eluent to obtain the title compound as a colorless oil: yield 6.0 g (50%). After stirring at 25° C. for 15 hr volatiles were removed in vacuo the resulting oily residue was purified by silica gel column chromatography