tert-butyl N-(2-fluoro-3-methoxyphenyl)carbamate

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%). The solvent was removed under reduced pressure the resulting mixture was heated at reflux for an additional 2 hours The reaction was cooled to ambient temperature The mixture was extracted with dichloromethane the combined dichloromethane extracts were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (2.50 g, 14.69 mmol) and DIEA (3.07 mL, 17.63 mmol) in a mixture of toluene (12 mL) and t-BuOH (12 mL) was stirred over 4 Å molecular sieves (3 g) for 1 hour at ambient temperature, followed by addition of diphenyl phosphoryl azide (3.9 mL, 17.63 mmol) and the mixture heated at reflux for 18 hours. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes) to afford tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 64% Yield). the mixture heated at reflux for 18 hours The cooled reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in ethyl acetate (50 mL) washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes)

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 Å molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+. the mixture was heated at reflux for 15 h The reaction mixture was cooled filtered To the filtrate was added ethyl acetate (200 mL) the solution was washed with water (2×100 mL) and brine (100 mL) The organic phase was separated dried over MgSO4 Filtration followed by concentration under reduced pressure

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 Å molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+. the mixture was heated at reflux for 15 h The reaction mixture was cooled filtered To the filtrate was added ethyl acetate (200 mL) the solution was washed with water (2×100 mL) and brine (100 mL) The organic phase was separated dried over MgSO4 Filtration followed by concentration under reduced pressure

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%). The solvent was removed under reduced pressure the resulting mixture was heated at reflux for an additional 2 hours The reaction was cooled to ambient temperature The mixture was extracted with dichloromethane the combined dichloromethane extracts were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (2.50 g, 14.69 mmol) and DIEA (3.07 mL, 17.63 mmol) in a mixture of toluene (12 mL) and t-BuOH (12 mL) was stirred over 4 Å molecular sieves (3 g) for 1 hour at ambient temperature, followed by addition of diphenyl phosphoryl azide (3.9 mL, 17.63 mmol) and the mixture heated at reflux for 18 hours. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes) to afford tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 64% Yield). the mixture heated at reflux for 18 hours The cooled reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in ethyl acetate (50 mL) washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%). The solvent was removed under reduced pressure the resulting mixture was heated at reflux for an additional 2 hours The reaction was cooled to ambient temperature The mixture was extracted with dichloromethane the combined dichloromethane extracts were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 Å molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+. the mixture was heated at reflux for 15 h The reaction mixture was cooled filtered To the filtrate was added ethyl acetate (200 mL) the solution was washed with water (2×100 mL) and brine (100 mL) The organic phase was separated dried over MgSO4 Filtration followed by concentration under reduced pressure

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 Å molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+. the mixture was heated at reflux for 15 h The reaction mixture was cooled filtered To the filtrate was added ethyl acetate (200 mL) the solution was washed with water (2×100 mL) and brine (100 mL) The organic phase was separated dried over MgSO4 Filtration followed by concentration under reduced pressure

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%). The solvent was removed under reduced pressure the resulting mixture was heated at reflux for an additional 2 hours The reaction was cooled to ambient temperature The mixture was extracted with dichloromethane the combined dichloromethane extracts were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

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

Procedure: A solution of 2-fluoro-3-methoxybenzoic acid (2.50 g, 14.69 mmol) and DIEA (3.07 mL, 17.63 mmol) in a mixture of toluene (12 mL) and t-BuOH (12 mL) was stirred over 4 Å molecular sieves (3 g) for 1 hour at ambient temperature, followed by addition of diphenyl phosphoryl azide (3.9 mL, 17.63 mmol) and the mixture heated at reflux for 18 hours. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes) to afford tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 64% Yield). the mixture heated at reflux for 18 hours The cooled reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in ethyl acetate (50 mL) washed with 1N HCl solution, saturated sodium bicarbonate solution, water and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes)