2,4-difluoro-6-methoxybenzaldehyde

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:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 3,5-Difluoroanisole (50 g, 0.35 mol) was charged to a 3-neck flask fitted with thermometer, dropping funnel and argon bubbler. Dichloromethane (200 mL) was added and the solution was cooled in ice-water. Titanium (IV) chloride (61.5 mL, 0.56 mol) was added dropwise (15 min), followed by dropwise addition of α,α-dichloromethyl methyl ether (31.5 mL, 0.35 mol) so that the temperature was maintained <10° C. (approx 20 min). The reaction was stirred in ice-water for a further 140 min, poured into ice-water (1 L), then extracted thrice with DCM. The organic solutions were washed with water, brine then dried (MgSO4) and evaporated. The crude product was purified using the Versaflash (80×300 mm SiO2 cartridge, gradient from DCM to 5% EtOAc) in 7 separate batches to give the title compound (34.5 g, 57%) as an orange solid. fitted with thermometer was maintained <10° C. (approx 20 min) extracted thrice with DCM The organic solutions were washed with water, brine then dried (MgSO4) evaporated The crude product was purified separate batches

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: To a solution of 3.5-difluoroanisole (25 g, 175 mmol) in dichloromethane (150 ml) cooled at 0° C. was added titanium tetrachloride (30.7 ml, 280 mmol). To this mixture was added dropwise over 10 minutes dichloromethyl methylether (15.8 ml, 175 mmol), and after complete addition the mixture was stirred at room temperature for 1 hour. The reaction was poured onto ice/water (500 ml) and extracted with DCM (3×300 ml). The combined DCM layers were washed with water (500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica-eluting with a gradient rising from 15% Et2O in isohexanes rising to 30% Et2O in isohexanes to give the title compound (11.2 g, 37%) as a white solid. after complete addition the mixture The reaction was poured onto ice/water (500 ml) extracted with DCM (3×300 ml) The combined DCM layers were washed with water (500 ml), saturated NaCl (200 ml) dried over Na2SO4 filtered evaporated The residue was purified by column chromatography on silica- eluting with a gradient

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 3,5-Difluoroanisole (50 g, 0.35 mol) was charged to a 3-neck flask fitted with thermometer, dropping funnel and argon bubbler. Dichloromethane (200 mL) was added and the solution was cooled in ice-water. Titanium (IV) chloride (61.5 mL, 0.56 mol) was added dropwise (15 min), followed by dropwise addition of α,αdichloromethyl methyl ether (31.5 mL, 0.35 mol) so that the temperature was maintained <10° C. (approx 20 min). The reaction was stirred in ice-water for a further 140 min, poured into ice-water (1 L), then extracted thrice with DCM. The organic solutions were washed with water, brine then dried (MgSO4) and evaporated. The crude product was purified using the Versaflash (80×300 mm SiO2 cartridge, gradient from DCM to 5% EtOAc) in 7 separate batches to give the title compound (34.5 g, 57%) as an orange solid. fitted with thermometer was maintained <10° C. (approx 20 min) extracted thrice with DCM The organic solutions were washed with water, brine then dried (MgSO4) evaporated The crude product was purified separate batches

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 3,5-Difluoroanisole (50 g, 0.35 mol) was charged to a 3-neck flask fitted with thermometer, dropping funnel and argon bubbler. Dichloromethane (200 mL) was added and the solution was cooled in ice-water. Titanium (IV) chloride (61.5 mL, 0.56 mol) was added dropwise (15 min), followed by dropwise addition of α,α-dichloromethyl methyl ether (31.5 mL, 0.35 mol) so that the temperature was maintained <10° C. (approx 20 min). The reaction was stirred in ice-water for a further 140 min, poured into ice-water (1 L), then extracted thrice with DCM. The organic solutions were washed with water, brine then dried (MgSO4) and evaporated. The crude product was purified using the Versaflash (80×300 mm SiO2 cartridge, gradient from DCM to 5% EtOAc) in 7 separate batches to give the title compound (34.5 g, 57%) as an orange solid. fitted with thermometer was maintained <10° C. (approx 20 min) extracted thrice with DCM The organic solutions were washed with water, brine then dried (MgSO4) evaporated The crude product was purified separate batches

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

Procedure: To a solution of 2,4-difluoro-6-methoxybenzaldehyde (Description 69, 11.2 g; 77.8 mmol) in anhydrous dichloromethane (500 ml) cooled at −78° C. was added boron tribromide (9.47 ml; 85.58 mmol) dropwise over 10 minutes. After complete addition the mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured onto ice/water (1 litre) and extracted with DCM (3×400 ml). The combined organic layers were washed with water (1 litre), saturated NaCl (500 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with 10% diethyl ether/isohexanes to give the title compound (9.2 g, 75%) as an orange oil. After complete addition the mixture The mixture was poured onto ice/water (1 litre) extracted with DCM (3×400 ml) The combined organic layers were washed with water (1 litre), saturated NaCl (500 ml) dried over Na2SO4 filtered evaporated The residue was purified by column chromatography on silica elution with 10% diethyl ether/isohexanes

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

Procedure: To a solution of 3.5-difluoroanisole (25 g; 175 mmol) in dichloromethane (150 ml) cooled at 0° C. was added titanium tetrachloride (30.7 ml; 280 mmol). To this mixture was added dropwise over 10 minutes dichloromethyl methylether (15.8 ml; 175 mmol), and after complete addition the mixture was stirred at room temperature for 1 hour. The reaction was poured onto ice/water (500 ml) and extracted with DCM (3×300 ml). The combined DCM layers were washed with water (500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica-eluting with a gradient rising from 15% Et2O in isohexanes rising to 30% Et2O in isohexanes to give the title compound (11.2 g, 37%) as a white solid. after complete addition the mixture The reaction was poured onto ice/water (500 ml) extracted with DCM (3×300 ml) The combined DCM layers were washed with water (500 ml), saturated NaCl (200 ml) dried over Na2SO4 filtered evaporated The residue was purified by column chromatography on silica- eluting with a gradient

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