2-fluoro-5-methoxyaniline

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

Procedure: 8-Fluoro-5-methoxy-2-methylquinoline was synthesized from 2-fluoro-5-methoxyaniline (30.0 g, 213 mmol) according to the procedures described above for 8-chloro-5-methoxy-2-methylquinoline hydrochloride (Intermediate 1, Step 1) with the following change: The hydrochloride salt was dissolved in dichloromethane (400 mL) and the pH of the resulting solution was adjusted to 8-9 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-petroleum ether) to afford 8-fluoro-5-methoxy-2-methylquinoline (25.2 g, 62%) as a yellow solid. MS (ESI, pos. ion) m/z 192 [M+H]+. The resulting mixture was extracted with dichloromethane the combined organic layers were dried over anhydrous sodium sulfate filtered concentrated under vacuum The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-petroleum ether)

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

Procedure: This procedure was patterned after that of Tietze and Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58° C. cooled in an ice bath After evaporation of the solvent extracted twice with ether The extracts were washed with water with brine, dried over magnesium sulfate concentrated The residue was recrystallized from hexane to afford 2.61 g the mother liquors were chromatographed on silica gel using 20:1 hexane/ether

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

Procedure: A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane/chloroform mixtures to afford 2.77 g (72%) of the subtitle compound. mp. 253-254° C. NMR (300 MHz, CDCl3): δ 6.88 (dd, J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H); 6.20 (dt, J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H). The catalyst was filtered off the solvent was evaporated filtered thourough a plug of silica gel evaporated This residue was chromatographed on silica gel

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

Procedure: A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane/chloroform mixtures to afford 2.77 g (72%) of the subtitle compound. mp. 253-254° C. NMR (300 MHz, CDCl3): δ 6.88 (dd, J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H); 6.20 (dt, J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H). The catalyst was filtered off the solvent was evaporated filtered thourough a plug of silica gel evaporated This residue was chromatographed on silica gel

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil. was added, dropwise over 0.5 h extracted with dichloromethane (3×150 mL) The combined extracts were dried (Na2SO4) evaporated in vacuo to give a brown oil Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid was hydrogenated at 20° C. Catalyst was removed by filtration the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL) The combined organic extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography on silica with 20-50% ether in hexane gradient elution

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil. was added, dropwise over 0.5 h extracted with dichloromethane (3×150 mL) The combined extracts were dried (Na2SO4) evaporated in vacuo to give a brown oil Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid was hydrogenated at 20° C. Catalyst was removed by filtration the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL) The combined organic extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography on silica with 20-50% ether in hexane gradient elution

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

Procedure: This procedure was patterned after that of Tietze and Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58° C. cooled in an ice bath After evaporation of the solvent extracted twice with ether The extracts were washed with water with brine, dried over magnesium sulfate concentrated The residue was recrystallized from hexane to afford 2.61 g the mother liquors were chromatographed on silica gel using 20:1 hexane/ether

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

Procedure: A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. The catalyst was filtered off the solvent was evaporated filtered thourough a plug of silica gel evaporated

Conditions: temp:19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-fluoro-5-methoxyaniline (35.15 g, 249 mmol) in acetic acid (99 mL) and water (177 mL) at 35° C. was added potassium cyanate (40 g, 0.49 mol) in water (170 mL) over 20 minutes under N2. The mixture was stirred at 40° C. for 20 min and at 18 to 20° C. for 2 h, and then quenched into water (500 mL). The crude product was filtered, washed with water (1.2 L), heptane (50 mL) and slurred in a mixture of tert-butylmethylether (100 mL) and ethyl acetate (5 mL) for 5 minutes at ambient temperature. The product was filtered, washed with tert-butylmethylether (30 mL) and dried in vacuo at 40° C. to give N-(2-Fluoro-5-methoxyphenyl)urea (31.75 g, 69%) as a light-brown solid. quenched into water (500 mL) The crude product was filtered washed with water (1.2 L), heptane (50 mL) slurred in a mixture of tert-butylmethylether (100 mL) and ethyl acetate (5 mL) for 5 minutes at ambient temperature The product was filtered washed with tert-butylmethylether (30 mL) dried in vacuo at 40° C.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2.0 L pressure reactor was charged with 10% Pd/C (50% wet paste, 10 g). A solution of 1,5-dibromo-3-fluoro-6-methoxy-5-nitrobenzene (50 g, 0.152 mol) in ethanol (absolute grade, 1.5 L) was added to the catalyst under N2. The stirred reaction mixture was subjected to three cycles of vacuum followed by N2 purge. The reaction mixture was evacuated prior to the introduction of H2 at a pressure of 4 bars. The reaction mixture was evacuated and H2 was introduced until a pressure of 7 bars was reached. The reaction mixture was stirred at 25° C. for 48 hours, with periodic injections of H2 to maintain the internal pressure at 7 bars (note that after 24 hours, the catalyst was replaced). After the reaction had reached completion, the catalyst was removed by filtration through 2 glass microfibre pads under an atmosphere of N2 and the filtrate was concentrated to dryness under reduced pressure at 45° C. The resulting dark orange solid was dissolved in water (500 mL) and the pH of the resulting solution adjusted to >12 using aqueous NaOH (1N, 400 mL). The resulting brown suspension was extracted with tert-butylmethylether (2×1 L). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo at 40° C. to afford 2-Fluoro-5-methoxyaniline (18.0 g, 84%) as a brown solid. The stirred reaction mixture purge The reaction mixture was evacuated The reaction mixture was evacuated H2 was introduced until a pressure of 7 bars to maintain the internal pressure at 7 bars (note that after 24 hours the catalyst was removed by filtration through 2 glass microfibre pads under an atmosphere of N2 the filtrate was concentrated to dryness under reduced pressure at 45° C The resulting dark orange solid was dissolved in water (500 mL) The resulting brown suspension was extracted with tert-butylmethylether (2×1 L) The combined organic extracts were washed with water (500 mL) dried over sodium sulfate filtered concentrated in vacuo at 40° C.

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

Procedure: This procedure was patterned after that of Tietze and Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58° C. cooled in an ice bath After evaporation of the solvent extracted twice with ether The extracts were washed with water with brine, dried over magnesium sulfate concentrated The residue was recrystallized from hexane to afford 2.61 g the mother liquors were chromatographed on silica gel using 20:1 hexane/ether

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

Procedure: A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. The catalyst was filtered off the solvent was evaporated filtered thourough a plug of silica gel evaporated