5-fluoro-2-hydroxybenzonitrile

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

Procedure: Intermediate (23t) (1.78 g, 13.0 mmol), 2-chloro-4-methyl-5-nitropyridine (2.31 g, 13.0 mmol) and potassium carbonate (1.80 g, 13.0 mmol) were dissolved in DMF (120 mL). When the mixture was warmed to 60° C., the colorless solution turned blue in 10 minutes. After 16 hours of stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and then diluted with 100 mL of Et2O. The inorganic precipitate was removed by filtration and washed with Et2O. The combined organic solution (600 mL total) was transferred to a separatory funnel and washed with 60 mL of water three times and with brine one time. The solution was dried over MgSO4 and then concentrated under reduced pressure to obtain crude brown solid. The crude solid was dissolved in MeOH (240 mL). To the solution was added 10% palladium on activated carbon under nitrogen atmosphere. Replacing nitrogen gas with hydrogen gas, the reaction mixture was stirred at room temperature (if the reaction did not proceed in 30 minutes, filtrated the Pd/C was filtered off and the reaction was set up again. After 1.5 hours of stirring, palladium on carbon was filtered off and washed with MeOH. The solution was concentrated under reduced pressure to obtain a pale yellow solid. The crude compound was purified on silica gel with EtOAc/hexane (1/1-3/2) to afford (1u) as a white solid (2.21 g, 70% yield over 2 steps). to cool down to room temperature The inorganic precipitate was removed by filtration washed with Et2O The combined organic solution (600 mL total) was transferred to a separatory funnel washed with 60 mL of water three times and with brine one time The solution was dried over MgSO4 concentrated under reduced pressure to obtain crude brown solid did not proceed in 30 minutes filtrated the Pd/C was filtered off After 1.5 hours of stirring palladium on carbon was filtered off washed with MeOH The solution was concentrated under reduced pressure to obtain a pale yellow solid The crude compound was purified on silica gel with EtOAc/hexane (1/1-3/2)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Intermediate (23t) (1.78 g, 13.0 mmol), 2-chloro-4-methyl-5-nitropyridine (2.31 g, 13.0 mmol) and potassium carbonate (1.80 g, 13.0 mmol) were dissolved in DMF (120 mL). When the mixture was warmed to 60° C., the colorless solution turned blue in 10 minutes. After 16 hours of stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and then diluted with 100 mL of Et2O. The inorganic precipitate was removed by filtration and washed with Et2O. The combined organic solution (600 mL total) was transferred to a separatory funnel and washed with 60 mL of water three times and with brine one time. The solution was dried over MgSO4 and then concentrated under reduced pressure to obtain crude brown solid. The crude solid was dissolved in MeOH (240 mL). To the solution was added 10% palladium on activated carbon under nitrogen atmosphere. Replacing nitrogen gas with hydrogen gas, the reaction mixture was stirred at room temperature (if the reaction did not proceed in 30 minutes, filtrated the Pd/C was filtered off and the reaction was set up again. After 1.5 hours of stirring, palladium on carbon was filtered off and washed with MeOH. The solution was concentrated under reduced pressure to obtain a pale yellow solid. The crude compound was purified on silica gel with EtOAc/hexane (1/1-3/2) to afford (1u) as a white solid (2.21 g, 70% yield over 2 steps). to cool down to room temperature The inorganic precipitate was removed by filtration washed with Et2O The combined organic solution (600 mL total) was transferred to a separatory funnel washed with 60 mL of water three times and with brine one time The solution was dried over MgSO4 concentrated under reduced pressure to obtain crude brown solid did not proceed in 30 minutes filtrated the Pd/C was filtered off After 1.5 hours of stirring palladium on carbon was filtered off washed with MeOH The solution was concentrated under reduced pressure to obtain a pale yellow solid The crude compound was purified on silica gel with EtOAc/hexane (1/1-3/2)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Fluorosalicylaldehyde oxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml) and refluxed for 5 hours. After completion of the reaction, acetic anhydride was distilled off under reduced pressure, followed by adding to the remaining oily substance, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), warming the mixture at 80° C. for 2 hours, allowing it to cool down to room temperature, adding 6N hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, which were then filtered off and recrystallized from methanol (30 ml) to obtain needle crystals (15.6 g) having a melting point of 121°-122° C. refluxed for 5 hours was distilled off under reduced pressure by adding to the remaining oily substance a solution of KOH (20 g) dissolved in water (100 ml) to cool down to room temperature adding 6N hydrochloric acid (50 ml) and water (200 ml) were then filtered off recrystallized from methanol (30 ml)

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

Procedure: 5-Fluorosalicylaldoxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml), followed by refluxing for 5 hours, distilling off acetic anhydride under reduced pressure after completion of the reaction, adding to the remaining oily material, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), heating the mixture at 80° C. for 2 hours, allowing to cool down to room temperature, adding 6N-hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, filtering the crystals, and recrystallizing from methanol (30 ml) to obtain acicular crystals (15.6 g). M.p. 121°~122° C. by refluxing for 5 hours distilling off acetic anhydride under reduced pressure after completion of the reaction adding to the remaining oily material filtering the crystals recrystallizing from methanol (30 ml)

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

Procedure: 5-Fluorosalicylaldoxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml), followed by refluxing for 5 hours, distilling off acetic anhydride under reduced pressure after completion of the reaction, adding to the remaining oily material, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), heating the mixture at 80° C. for 2 hours, allowing to cool down to room temperature, adding 6N-hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, filtering the crystals, and recrystallizing from methanol (30 ml) to obtain acicular crystals (15.6 g). M.p. 121°~122° C. by refluxing for 5 hours distilling off acetic anhydride under reduced pressure after completion of the reaction adding to the remaining oily material filtering the crystals recrystallizing from methanol (30 ml)

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

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