2-Fluoro-3-methoxybenzyl alcohol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: Triphenylphosphine (11.1 g) was added to a solution of the subtitle product of step ii) (5.0 g) in DCM (200 ml) followed by the portionwise addition of carbon tetrabromide (14.0 g). The reaction was stirred for 4 h before the addition of further triphenylphosphine (2.0 g) and carbon tetrabromide (2.0 g) and stirring maintained for 1 h. The mixture was concentrated to 30 ml volume and diluted in Et2O (300 ml). The solid precipitate was filtered and washed with Et2O (3×) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (10% Et2O/iso-hexane) to afford the subtitle compound as a clear oil. Yield: 5.2 g. maintained for 1 h The mixture was concentrated to 30 ml volume diluted in Et2O (300 ml) The solid precipitate was filtered washed with Et2O (3×) the filtrate concentrated in vacuo The residue was purified by column chromatography (10% Et2O/iso-hexane)

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

実験手順: Lithium aluminium hydride (83.5 ml, 1M solution in THF) was added dropwise to a suspension of the subtitle product of step i) (7.1 g) in Et2O (180 ml) at a rate that maintained gentle reflux. Upon complete addition the reaction was stirred for 1.5 h. 15% sodium hydroxide solution was added dropwise until no effervescence was observed. The resulting white precipitate was filtered and the filtrate diluted with H2O (100 ml). The organics were removed in vacuo and the residue extracted with Et2O (100 ml). The organics were washed with 2M sodium hydroxide solution (150 ml), H2O (150 ml), brine (150 ml), dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a white crystalline solid. Yield: 5.5 g. maintained gentle reflux Upon complete addition the reaction The resulting white precipitate was filtered the filtrate diluted with H2O (100 ml) The organics were removed in vacuo the residue extracted with Et2O (100 ml) The organics were washed with 2M sodium hydroxide solution (150 ml), H2O (150 ml), brine (150 ml) dried (MgSO4) concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

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: 2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The flask was capped and the reaction stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NMR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m). hydrochloric acid gas was bubbled through the solution for 3 minutes The flask was capped The reaction mixture was extracted with ether dried over MgSO4 concentrated in vacuo

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

実験手順: 2-Fluoro-3-methoxybenzoic acid from Step 1 (16.65 g, 98 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled in an ice bath, and treated with borane dimethyl sulfide complex (19 mL, 190 mmol). The reaction was stirred at room temperature for 4.2 hours, quenched by the slow addition of methanol, and concentrated in vacuo. The residue was dissolved in ethyl acetate, treated with 3N hydrochloric acid and filtered through diatomaceous earth. The organic layer of the filtrate was collected, washed with NaHCO3, brine, dried over MgSO4 and reconcentrated in vacuo to give 2-fluoro-3-methoxybenzyl alcohol (12.35 g, 81%) as a white solid: mp 53°-57° C.; 1H NMR (acetone-d6) 300 MHz 7.07 (m, 3H) 4.67 (d, J=5.8 Hz, 2H) 4.24 (t, J=5.8 Hz, 1H) 3.86 (s, 3H); 19F NMR (acetone-d6) 300 MHz -144.77 (m). cooled in an ice bath treated with borane dimethyl sulfide complex (19 mL, 190 mmol) quenched by the slow addition of methanol concentrated in vacuo The residue was dissolved in ethyl acetate treated with 3N hydrochloric acid filtered through diatomaceous earth The organic layer of the filtrate was collected washed with NaHCO3, brine dried over MgSO4

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

実験手順: 2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The flask was capped and the reaction stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NMR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m). hydrochloric acid gas was bubbled through the solution for 3 minutes The flask was capped The reaction mixture was extracted with ether dried over MgSO4 concentrated in vacuo

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

実験手順: 2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The flask was capped and the reaction stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NMR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m). hydrochloric acid gas was bubbled through the solution for 3 minutes The flask was capped The reaction mixture was extracted with ether dried over MgSO4 concentrated in vacuo