2,6-difluoro-4-methoxybenzaldehyde

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

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

Procedure: Butyl-[1-(2,6-difluoro-4-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): yellow oil; MS (ISP): 228.4 ([M+H]+, 100%).

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

Procedure: Butyl-[1-(2,6-difluoro-4-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): yellow oil; MS (ISP): 228.4 ([M+H]+, 100%).

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

Procedure: A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. Thereto was added 2,6-difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) and the mixture was stirred for 4 hr while allowing to warm to room temperature. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needles. cooling for 10 min washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution dried over magnesium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5)

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

Procedure: A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. Thereto was added 2,6-difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) and the mixture was stirred for 4 hr while allowing to warm to room temperature. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needles. cooling for 10 min washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution dried over magnesium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5)

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

Procedure: The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-difluoro-4-methoxybenzaldehyde (0.688 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.2 mL, 8.6 mmol), di-(imidazol-1-yl)methanone (0.761 g, 4.69 mmol) as described in method 2. The product was purified by means of FPLC. The compound was synthesized The product was purified by means of FPLC

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

Procedure: (Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3 H), 6.47 (d, J=10.55 Hz, 2 H), 10.17 (s, 1 H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3 H) 6.43-6.51 (m, 2 H) 10.30 (s, 1 H)], both as white solids. (Intermediates 26A and 26B were prepared in a similar manner to the preparation Upon completion of addition The resulting mixture was extracted with dichloromethane (3×50 mL) The combined organics were washed with H2O (50 mL), brine (50 mL) dried over Na2SO4 filtered The volatiles were removed under reduced pressure to provide a residue

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

Procedure: The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-difluoro-4-methoxybenzaldehyde (0.688 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.2 mL, 8.6 mmol), di-(imidazol-1-yl)methanone (0.761 g, 4.69 mmol) as described in method 2. The product was purified by means of FPLC. The compound was synthesized The product was purified by means of FPLC

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

Procedure: Butyl-[1-(2,6-difluoro-4-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): yellow oil; MS (ISP): 228.4 ([M+H]+, 100%).

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

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

Procedure: (Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H), 6.47 (d, J=10.55 Hz, 2H), 10.17 (s, 1H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.43-6.51 (m, 2H) 10.30 (s, 1H)], both as white solids. (Intermediates 26A and 26B were prepared in a similar manner to the preparation Upon completion of addition The resulting mixture was extracted with dichloromethane (3×50 mL) The combined organics were washed with H2O (50 mL), brine (50 mL) dried over Na2SO4 filtered The volatiles were removed under reduced pressure to provide a residue

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

Procedure: The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-difluoro-4-methoxybenzaldehyde (0.688 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.2 mL, 8.6 mmol), di-(imidazol-1-yl)methanone (0.761 g, 4.69 mmol) as described in method 2. The product was purified by means of FPLC. The compound was synthesized The product was purified by means of FPLC