1-(3-bromo-5-fluorophenyl)ethanol

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 solution of (±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with several volumes of pentane, and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7. filtered to remove the undissolved solids which The organics were concentrated purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil

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

Procedure: The title compound was prepared from 4-bromo-2,6-dichlorobenzaldehyde (prepared according to WO 2008/021851) by reaction with methylmagnesium bromide following the procedure for 1-(3-bromo-5-fluorophenyl)ethanol as described.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into the THF (8 ml) solution of 3-bromo-5-fluorobenzaldehyde (374 mg, 1.84 mmol) which was cooled in ice/water bath was added methylmagnesium bromide in Et2O (3.0 M, 0.92 ml) dropwise under an atmosphere of nitrogen. The combined mixture was stirred at 0° C. for 1 h and then at rt for 1 h. After that time, the mixture was quenched with saturated NH4Cl (10 ml) followed by water (10 ml), extracted with EtOAc (2×25 ml). The extracts were washed with water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to give a beige oil. It was purified by chromatography on silica gel (15 g) eluting with 10% (100 ml), 15% (100 ml), 20% (100 ml) and 25% (100 ml) EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.47 (d, J=6.4 Hz, 3H), 1.87 (d, J=3.6 Hz, 1H), 4.83-4.90 (m, 1H), 7.02-7.06 (m, 1H), 7.14 (td, J=2.0 & 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H). MS (ES+): m/z 201.22/203.18 [MH+−H2O]. HPLC: tR=3.07 min (polar—5 min, ZQ3). at rt for 1 h After that time, the mixture was quenched with saturated NH4Cl (10 ml) extracted with EtOAc (2×25 ml) The extracts were washed with water (2×15 ml), brine (15 ml) dried over MgSO4 filtered concentrated in vacuo to give a beige oil It was purified by chromatography on silica gel (15 g) eluting with 10% (100 ml), 15% (100 ml), 20% (100 ml) and 25% (100 ml) EtOAc/hexane

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

Procedure: To a solution of 3-bromo-5-fluorobenzaldehyde (6.0 g, 29.6 mmol, prepared according to patent WO 0066556) in THF (100 ml) was added dropwise at 0° C. methylmagnesiumchloride (3N in THF, 12 ml). The reaction mixture was stirred for 3 hours at room temperature and then sat. NH4Cl solution was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel to yield 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 45%), 1H-NMR (300 MHz, CDCl3): δ=7.31 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 4.82-4.94 (m, 1H), 1.51 (d, 3H). The aqueous phase was extracted twice with ethyl acetate The combined organic layers were washed with water dried over MgSO4 filtered the solvent was removed in vacuo The crude product was purified by chromatography over silica gel

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

Procedure: To a solution of 3-bromo-5-fluorobenzaldehyde (6.0 g, 29.6 mmol, prepared according to patent WO 0066556) in THF (100 ml) was added dropwise at 0° C. methylmagnesiumchloride (3N in THF, 12 ml). The reaction mixture was stirred for 3 hours at room temperature and then sat. NH4Cl solution was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel to yield 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 45%), 1H-NMR (300 MHz, CDCl3): δ=7.31 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 4.82-4.94 (m, 1H), 1.51 (d, 3H). The aqueous phase was extracted twice with ethyl acetate The combined organic layers were washed with water dried over MgSO4 filtered the solvent was removed in vacuo The crude product was purified by chromatography over silica gel

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

Procedure: To a solution of 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 13.2 mmol) in methylene chloride (150 ml) was added at room temperature pyridinium dichromate (3.98 g). The reaction mixture was stirred for 4 hours at room temperature and the solvent was removed in the presence of silica gel. The crude product was purified by chromatography over silica gel to provide 1-(3-bromo-5-fluoro-phenyl)-ethanone (1.39 g, 45%) as a light yellow solid, MS: m/e=216.1 (M+). the solvent was removed in the presence of silica gel The crude product was purified by chromatography over silica gel

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

Procedure: To a solution of (±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with several volumes of pentane, and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7. filtered to remove the undissolved solids which The organics were concentrated purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil

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

Procedure: To a solution of (±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with several volumes of pentane, and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7. filtered to remove the undissolved solids which The organics were concentrated purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil

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

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