4-hydroxy-3-iodobenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-1-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25° C. for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s, 1H); MS (ESI) m/e 255 (M+H)+. the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h The reaction mixture was cooled filtered through celite concentrated under reduced pressure purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL conc. ammonium hydroxide was added and contents were allowed to stir at 25° C. for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25° C. for 18 h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+. was added was quickly added to stir at 25° C. for 18 h at which time contents were filtered The filtrate was concentrated under reduced pressure redissolved in 500 mL dichloromethane The organic layer was then washed twice with 250 mL water dried concentrated under reduced pressure

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL conc. ammonium hydroxide was added and contents were allowed to stir at 25° C. for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25° C. for 18 h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+. was added was quickly added to stir at 25° C. for 18 h at which time contents were filtered The filtrate was concentrated under reduced pressure redissolved in 500 mL dichloromethane The organic layer was then washed twice with 250 mL water dried concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3×2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCl3) 7.96 (d, 1H, 1.9 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.03 (d, 1H, J=8.5 Hz); 6.03 (s, 1H); The precipitate formed was filtered off filtrate was evaporated to dryness under reduced pressure The residue was treated with H2O (3 ml) The precipitate formed was filtered off washed with cold H2O (3×2 ml) dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of the product of Step A (0.3 g; 1.22 mmol) in HMDSA (2 ml) and saccharine (0.1 g) was refluxed under N2 until reaction became homogenous (˜30 min). After cooling to room temperature, the HMDSA was removed in vacuo and the residue was diluted to 4 ml with anhydrous THF. At the same time ZnCl2 (0.2 g; 1.47 mmol) was heated to ˜110° C., in separate flask, in vacuo, cooled to room temperature under N2 and diluted to 4 ml with anhydrous THF. To it 0.5 M prop-1-ynyl-magnesium bromide in THF (4.9 ml; 2.45 mmol) was added at room temperature and this was stirred for 10 min under N2. To it a solution of silinated product of Step A was added, followed by Pd(PPh3)4 (0.11 g; 0.095 mmol) and CuI (0.05 g; 0.26 mmol). After stirring for 1 h at room temperature under N2, MeOH (5 ml) was added and solvents were removed under reduced pressure. The residue was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give title compound (0.16 g; 78%), as colourless solid. 1H-NMR (CDCl3) 2.14 (s, 3H); 6.26 (s, 1H); 6.97 (d, 1H, J=8.5 Hz); 7.46 (dd, 1H, J=2.1 Hz, 8.5 Hz); 7.57 (d, 1H, 2.1 Hz). was refluxed under N2 until reaction (˜30 min) the HMDSA was removed in vacuo the residue was diluted to 4 ml with anhydrous THF cooled to room temperature under N2 After stirring for 1 h at room temperature under N2 solvents were removed under reduced pressure The residue was diluted to 20 ml with EtOAc washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4 filtered filtrate evaporated to dryness under reduced pressure The residue was purified by FCC (SiO2, CH2Cl2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of the product of Step A (0.3 g; 1.22 mmol) in HMDSA (2 ml) and saccharine (0.1 g) was refluxed under N2 until reaction became homogenous (˜30 min). After cooling to room temperature, the HMDSA was removed in vacuo and the residue was diluted to 4 ml with anhydrous THF. At the same time ZnCl2 (0.2 g; 1.47 mmol) was heated to ˜110° C., in separate flask, in vacuo, cooled to room temperature under N2 and diluted to 4 ml with anhydrous THF. To it 0.5 M prop-1-ynyl-magnesium bromide in THF (4.9 ml; 2.45 mmol) was added at room temperature and this was stirred for 10 min under N2. To it a solution of silinated product of Step A was added, followed by Pd(PPh3)4 (0.11 g; 0.095 mmol) and CuI (0.05 g; 0.26 mmol). After stirring for 1 h at room temperature under N2, MeOH (5 ml) was added and solvents were removed under reduced pressure. The residue was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give title compound (0.16 g; 78%), as colourless solid. 1H-NMR (CDCl3) 2.14 (s, 3H); 6.26 (s, 1H); 6.97 (d, 1H, J=8.5 Hz); 7.46 (dd, 1H, J=2.1 Hz, 8.5 Hz); 7.57 (d, 1H, 2.1 Hz). was refluxed under N2 until reaction (˜30 min) the HMDSA was removed in vacuo the residue was diluted to 4 ml with anhydrous THF cooled to room temperature under N2 After stirring for 1 h at room temperature under N2 solvents were removed under reduced pressure The residue was diluted to 20 ml with EtOAc washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4 filtered filtrate evaporated to dryness under reduced pressure The residue was purified by FCC (SiO2, CH2Cl2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3×2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCl3) 6.03 (s, 1H); 7.03 (d, 1H, J=8.5 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.96 (d, 1H, 1.9 Hz). The precipitate formed was filtered off filtrate was evaporated to dryness under reduced pressure The residue was treated with H2O (3 ml) The precipitate formed was filtered off washed with cold H2O (3×2 ml) dried in vacuo

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-1-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25° C. for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s, 1H); MS (ESI) m/e 255 (M+H)+. the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h The reaction mixture was cooled filtered through celite concentrated under reduced pressure purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL conc. ammonium hydroxide was added and contents were allowed to stir at 25° C. for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25° C. for 18 h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+. was added was quickly added to stir at 25° C. for 18 h at which time contents were filtered The filtrate was concentrated under reduced pressure redissolved in 500 mL dichloromethane The organic layer was then washed twice with 250 mL water dried concentrated under reduced pressure

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL conc. ammonium hydroxide was added and contents were allowed to stir at 25° C. for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25° C. for 18 h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+. was added was quickly added to stir at 25° C. for 18 h at which time contents were filtered The filtrate was concentrated under reduced pressure redissolved in 500 mL dichloromethane The organic layer was then washed twice with 250 mL water dried concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Hydroxy-3-iodobenzonitrile was prepared by the method analogous to Preparation 341 above using N-iodosuccinimide, acetic acid, sulfuric acid and 4-Hydroxybenzonitrile. Purified by ISCO™ (80 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to yield the title compound. 4-Hydroxy-3-iodobenzonitrile was prepared by the method analogous to Preparation 341 Purified by ISCO™ (80 g SiO2) eluting with ethyl acetate