3-fluoro-4-(2-methoxyethoxy)aniline

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:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 10.8 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (2.5 mL, 32.4 mol, 3.0 eq.) and phenyl chloroformate (1.36 mL, 10.8 mmol, 1.0 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and evaporated again. The resulting residue was purified by column chromatography using EtOAc/PE (1:4) as eluent to yield phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (2.7 g, 76.8%) as a white solid (TLC system: EtOAc/PE (3:7), Rf: 0.5). The solvent was evaporated the residue diluted with EtOAc (50 mL) washed with water (100 mL), brine (20 mL) evaporated again The resulting residue was purified by column chromatography

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

Procedure: To a stirred solution of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (2.5 g, 11.62 mmol, 1.0 eq.) in ethanol (20 mL) was added 10% Pd/C (500 mg) and stirred in hydrogen gas atmosphere for 16 h at RT. The catalyst was filtered over a celite pad and the filtrate was concentrated to get 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 93.9%; TLC system: EtOAc/PE (3:7), Rf: 0.3). The catalyst was filtered over a celite pad the filtrate was concentrated

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

Procedure: A mixture of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (12.0 g , 55.7 mmol), iron powder (10.3 g, 180 mmol) and ammonium chloride (14.5 g , 270 mmol) in 170 mL of ethanol and 50 mL of water is heated at reflux for 1.5 hours then filtered hot through a pad of Diatomaceous earth, washing with ethanol. The filtrate is cooled to room temperature and the precipitated solids are removed by filtration. The filtrate is concentrated to a small volume and partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide 9.45 g of 3-fluoro-4-(2-methoxyethoxy)aniline as a brown liquid. is heated at reflux for 1.5 hours then filtered hot through a pad of Diatomaceous earth washing with ethanol the precipitated solids are removed by filtration The filtrate is concentrated to a small volume partitioned between ethyl acetate and water The organic layer is dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: In a procedure analogous to Example 125, 250 mg of the title compound was prepared from 2-fluoro-1-{[2-(methyloxy)ethyl]oxy}-4-nitrobenzene as brown oil. 1H NMR (CDCl3, 400 MHz) δ 3.40 (s, 3H), 3.51 (brs, 2H), 3.67 (d, 2H, J=4.7 Hz), 4.06 (t, 2H, J=4.7 Hz), 6.32 (d, 1H, J=8.6 Hz), 6.41 (dd, 1H, J=12.6 and 2.8 Hz), and 6.8 (t, 1H, J=9.0 Hz).

Conditions: temp:0.00; pressure:0.00; stir: