2-(diethoxyphosphorylmethyl)-1,4-difluorobenzene

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

実験手順: Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 2-(bromomethyl)-4-chloropyrimidine. Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min. Mass spec.: 265.1 (MH)+. Prepared

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

実験手順: Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 4-(bromomethyl)-6-chloropyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.68 (dd, J=2.3, 1.1 Hz, 1H), 4.21-3.88 (m, 4H), 3.74-3.45 (m, 2H), 1.20 (t, J=7.0 Hz, 6H), Mass spec.: 265.1 (MH)+. Prepared

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

実験手順: Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 2-bromo-4-(bromomethyl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.69-8.58 (m, 1H), 7.67-7.44 (m, 1H), 4.14-3.91 (m, 4H), 3.62-3.43 (m, 2H), 1.42-1.09 (m, 6H), Mass spec.: 310.1 (MH)+. Prepared

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

実験手順: To a stirred solution of diethyl 2,5-difluorobenzylphosphonate (63.5 g, 240 mmol) and 5-bromonicotinaldehyde (50.7 g, 264 mmol) in tetrahydrofuran (1923 ml) was added potassium tert-butoxide in tetrahydrofuran (312 ml, 312 mmol) at −10° C. After three hours, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 16 hours at which time the reaction mixture was diluted with ether (800 mL) and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to provide a yellow wax to which was added 300 mL of hexane and after sonication filtered to provide (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (54 g, 173 mmol, 72.1%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=1.8 Hz, 1H), 8.63 (d, J=2.1 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 7.67 (ddd, J=9.4, 6.0, 3.2 Hz, 1H), 7.56-7.48 (m, 1H), 7.46-7.40 (m, 1H), 7.34 (td, J=9.6, 4.6 Hz, 1H), 7.24 (tt, J=8.3, 3.6 Hz, 1H). MS Anal. Calcd. for [M+H]+ C13H9BrF2N: 296.0. found 298.1. was continued for another 16 hours at which time washed with H2O The organic layer was dried over anhydrous magnesium sulfate filtered concentrated to provide a yellow wax to which after sonication filtered

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-(bromomethyl)-1,4-difluorobenzene (3 g, 14.49 mmol) and triethyl phosphite (7.72 ml, 43.5 mmol) was heated to 160° C. with stirring for 4 hours, cooled to ambient temperature and concentrated under high vacuum to remove most triethyl phosphite. The resulting residue was purified by column chromatography (20% to 30% EtOAc/Toluene) providing diethyl 2,5-difluorobenzylphosphonate (3.76 g, 13.52 mmol, 93% yield) as colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.10 (m, 3H), 4.05-3.91 (m, 4H), 3.31-3.20 (m, 2H), 1.18 (t, J=7.0 Hz, 6H). MS Anal. Calcd. for [M+H]+ C11H16F2O3P: 265.2. found 265.3. cooled to ambient temperature concentrated under high vacuum to remove most triethyl phosphite The resulting residue was purified by column chromatography (20% to 30% EtOAc/Toluene)