1-[chloromethyl(ethoxy)phosphoryl]oxyethane

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a solution of 4-Piperazin-1-ylmethyl-benzoic acid (4c) and chloromethyl-phosphonic acid diethyl ester (4d) in ethanol was added potassium carbonate. The resulting reaction mixture was refluxed, then cooled to room temperature, diluted with brine, acidified to pH˜4, and extracted with EtOAc until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated on rotary evaporator. The desired product was purified by silica gel flash chromatography. The resulting reaction mixture was refluxed extracted with EtOAc until the aqueous layer The combined organics were dried over MgSO4 concentrated on rotary evaporator The desired product was purified by silica gel flash chromatography

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (1.5g, 80%, 50 mmol) was added in portions to a stirred solution of thioethanol (3.9 g, 50 mmol) in dry tetrahydrofuran (50 ml) at room temperature. The mixture was stirred for 0.5 hours then freshly ground and dried potassium iodide (0.5 g, 3.0 mmol) was added, followed by diethylchloromethylphosphonate (9.3 g, 50 mmol) in dry tetrahydrofuran (25 ml) over 5 minutes (exothermic reaction, temperature rose to 50° C.). The reaction mixture was then stirred and heated at 80° C. for 18 hours. The cooled reaction was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel eluting with chloroform, to give the title compound as an oil (8.0 g, 79%); υmax (Film) 3380, 2980, 2900, 2860, 1475 and 1440 cm-1 ; δH (CDCl3) 1.35 (6H, t, J 7Hz, 2 × CH3), 2.80 (2H, d, J 13Hz, PCH2S), 2.87 (2H, t, J 5Hz, SCH2CH2), 3.8 (2H, br s, CH2OH), 3.92 (lH, br s, D2O exchangeable, OH), 4.2 (4H, m, 2 × CH2OP), (exothermic reaction, temperature rose to 50° C.) The reaction mixture was then stirred The cooled reaction was evaporated to dryness in vacuo the residue was purified by column chromatography on silica gel eluting with chloroform

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (1.5g, 80%, 50 mmol) was added in portions to a stirred solution of thioethanol (3.9 g, 50 mmol) in dry tetrahydrofuran (50 ml) at room temperature. The mixture was stirred for 0.5 hours then freshly ground and dried potassium iodide (0.5 g, 3.0 mmol) was added, followed by diethylchloromethylphosphonate (9.3 g, 50 mmol) in dry tetrahydrofuran (25 ml) over 5 minutes (exothermic reaction, temperature rose to 50° C.). The reaction mixture was then stirred and heated at 80° C. for 18 hours. The cooled reaction was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel eluting with chloroform, to give the title compound as an oil (8.0 g, 79%); υmax (Film) 3380, 2980, 2900, 2860, 1475 and 1440 cm-1 ; δH (CDCl3) 1.35 (6H, t, J 7Hz, 2 × CH3), 2.80 (2H, d, J 13Hz, PCH2S), 2.87 (2H, t, J 5Hz, SCH2CH2), 3.8 (2H, br s, CH2OH), 3.92 (lH, br s, D2O exchangeable, OH), 4.2 (4H, m, 2 × CH2OP), (exothermic reaction, temperature rose to 50° C.) The reaction mixture was then stirred The cooled reaction was evaporated to dryness in vacuo the residue was purified by column chromatography on silica gel eluting with chloroform

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

実験手順: To a solution of 4-Piperazin-1-ylmethyl-benzoic acid (4c) and chloromethyl-phosphonic acid diethyl ester (4d) in ethanol was added potassium carbonate. The resulting reaction mixture was refluxed, then cooled to room temperature, diluted with brine, acidified to pH˜4, and extracted with EtOAc until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated on rotary evaporator. The desired product was purified by silica gel flash chromatography. The resulting reaction mixture was refluxed extracted with EtOAc until the aqueous layer The combined organics were dried over MgSO4 concentrated on rotary evaporator The desired product was purified by silica gel flash chromatography

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

実験手順: To a solution of 4-Piperazin-1-ylmethyl-benzoic acid (4c) and chloromethyl-phosphonic acid diethyl ester (4d) in ethanol was added potassium carbonate. The resulting reaction mixture was refluxed, then cooled to room temperature, diluted with brine, acidified to pH˜4, and extracted with EtOAc until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated on rotary evaporator. The desired product was purified by silica gel flash chromatography. The resulting reaction mixture was refluxed extracted with EtOAc until the aqueous layer The combined organics were dried over MgSO4 concentrated on rotary evaporator The desired product was purified by silica gel flash chromatography

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

実験手順: Dibutyl diethyl methylenediphosphonate was prepared in 43% yield by reacting sodium dibutyl phosphite with diethyl chloromethylphosphonate, bp=140° (0.05 mmHg), (Kugelrohr).

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

実験手順: A solution of 2-nitro-3-methoxypyridine (300 mg, 1.95 mmol) and diethyl chloromethylphosphonate (363 mg, 1.95 mmol) in DMSO (4 mL) was added dropwise to vigorously stirred solution of t-BuONa (0.561 g, 5.84 mmol) in DMSO (4 mL) at room temperature. The reaction mixture turned to deep orange immediately. Stirring was continued for 30 min, then the mixture was poured into 1 M HCl (aq) (10 mL). The product was extracted into ether (3×30 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (3% MeOH in DCM) to afford 102.6 mg of diethyl [(6-amino-5-methoxypyridin-3-yl)methyl]phosphonate (yield: 17%). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=6.8 Hz, 6 H), 3.45 (d, J=22.4 Hz, 2 H), 4.00 (s, 3 H), 4.09-4.17 (m, 4 H), 7.79 (t, J=2.4 Hz, 1 H), 7.97 (t, J=2.4 Hz, 1 H). MS (ES+): m/z 305.07 [MH+]. HPLC: tR=1.17 min (UPLC TOF, polar—3 min). The product was extracted into ether (3×30 mL) dried over MgSO4 concentrated purified by silica gel chromatography (3% MeOH in DCM)

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

実験手順: A solution of 2-nitro-3-methoxypyridine (300 mg, 1.95 mmol) and diethyl chloromethylphosphonate (363 mg, 1.95 mmol) in DMSO (4 mL) was added dropwise to vigorously stirred solution of t-BuONa (0.561 g, 5.84 mmol) in DMSO (4 mL) at room temperature. The reaction mixture turned to deep orange immediately. Stirring was continued for 30 min, then the mixture was poured into 1 M HCl (aq) (10 mL). The product was extracted into ether (3×30 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (3% MeOH in DCM) to afford 102.6 mg of diethyl [(6-amino-5-methoxypyridin-3-yl)methyl]phosphonate (yield: 17%). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=6.8 Hz, 6 H), 3.45 (d, J=22.4 Hz, 2 H), 4.00 (s, 3 H), 4.09-4.17 (m, 4 H), 7.79 (t, J=2.4 Hz, 1 H), 7.97 (t, J=2.4 Hz, 1 H). MS (ES+): m/z 305.07 [MH+]. HPLC: tR=1.17 min (UPLC TOF, polar—3 min). The product was extracted into ether (3×30 mL) dried over MgSO4 concentrated purified by silica gel chromatography (3% MeOH in DCM)

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

実験手順: A solution of 2-methoxy-3-nitropyridine (6.92 g, 44.9 mmol) and diethyl chloromethylphosphonate (7.00 mL, 44.9 mmol) in 40 mL DMSO was added drop wise to a stirred mixture of potassium tert-butoxide (15.1 g, 134.6 mmol) and 40 mL DMSO. The mixture was stirred at room temperature for 30 minutes, after which, it was poured into a 1N HCl/ice mixture and extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM:EtOAc1:1). The slower eluting regioisomer was collected and confirmed to be the desired product (750 mg, 5.5% yield). MS (ES+): m/z 305.16 (100) [MH+]; HPLC: tR=1.16 min (UPLC, Analytical). extracted with methylene chloride The combined organic layers were washed with water, brine dried over anhydrous sodium sulfate filtered concentrated purified by column chromatography (DCM:EtOAc1:1) The slower eluting regioisomer was collected

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

実験手順: A solution of 2-methoxy-3-nitropyridine (6.92 g, 44.9 mmol) and diethyl chloromethylphosphonate (7.00 mL, 44.9 mmol) in 40 mL DMSO was added drop wise to a stirred mixture of potassium tert-butoxide (15.1 g, 134.6 mmol) and 40 mL DMSO. The mixture was stirred at room temperature for 30 minutes, after which, it was poured into a 1N HCl/ice mixture and extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM:EtOAc1:1). The slower eluting regioisomer was collected and confirmed to be the desired product (750 mg, 5.5% yield). MS (ES+): m/z 305.16 (100) [MH+]; HPLC: tR=1.16 min (UPLC, Analytical). extracted with methylene chloride The combined organic layers were washed with water, brine dried over anhydrous sodium sulfate filtered concentrated purified by column chromatography (DCM:EtOAc1:1) The slower eluting regioisomer was collected

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

実験手順: To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0° C. was added 1-methyl-2-hydroxymethyl-4-phenyl-5-[4-pyridinyl]imidazole (0.100 g, 0.377 mmol) in DMF. The resulting bright yellow solution was stirred at 0° C. for 0.5 h when diethyl chloromethylphosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL of HMPA was added. The resulting mixture was stirred at 0° C. for 15 min and then warmed to rt. After 5 h, the solution was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a light amber oil (0.088 g, 56%): ESMS (mnz): 416 (M++H). was added warmed to rt After 5 h the solution was partitioned between CH2Cl2 and H2O The organic extract was washed with aqueous NaCl dried (MgSO4) The solvent was removed in vacuo the residue was purified by flash chromatography eluting with 50:1 CH2Cl2/MeOH