4-chloro-3-fluorobenzaldehyde

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:

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

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

Procedure: In a manner analogous to Preparation 1, tosylmethylisocyanide (0.30 g, 1.52 mmol), 4-chloro-3-fluorobenzaldehyde (0.25 g, 1.60 mmol) and NaCN (10 mg, 0.20 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 373.5 (M+Na+).

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

Procedure: To a solution of 25.0 g (158 mmol) 4-chloro-3-fluorobenzaldehyde in 130 ml methanol and 175 ml methanol saturated with ammonia were added 54.9 ml (52.7 g, 185 mmol) tetraisopropyl orthotitanate and the mixture stirred at ambient temperature for 1.5 hours. Then 20.35 ml (16.14 g, 163 mmol) trimethylsilyl cyanide were added drop-wise and the resulting mixture stirred at ambient temperature for further 2 hours. The reaction mixture was poured onto 1500 ml iced water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash-chromatography on silica gel with a gradient of heptane and 0 to 50% ethyl acetate. rac-Amino-(4-chloro-3-fluoro-phenyl)-acetonitrile was obtained as orange oil: MS (ISN): 183.2 (M−H)−. the resulting mixture stirred at ambient temperature for further 2 hours extracted with ethyl acetate The combined organic phases were washed with brine dried over Na2SO4 evaporated The crude product was purified by flash-chromatography on silica gel with a gradient of heptane and 0 to 50% ethyl acetate

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: 4-Chloro-3-fluorobenzaldehyde (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid. being extracted three times with dichloromethane The pooled organic phases were washed once with water, once with brine dried over magnesium sulfate filtered the solvent removed under reduced pressure

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

Procedure: To a solution of 4-chloro-3-fluorobenzaldehyde (50.0 g) and methyl acrylate (42.6 mL) in acetonitrile (158 mL) was added 1,4-diazabicyclo[2.2.2]octane (10.6 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (69.1 g). The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel chromatography (hexane/ethyl acetate)

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

Procedure: Sodium chlorite (17 g) was added portionwise to a mixture solution composed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g). washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride After the resultant organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane