5-fluoro-2-phenylmethoxybenzonitrile

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). 1H NMR δ (CDCl3) 7.49-7.44 (2H, m), 7.42-7.36 (2H, m), 7.36-7.29 (1H, m), 6.99-6.92 (1H, m), 6.88-6.82 (2H, m), 5.13 (2H, s), 2.13 (2H, s), 1.00-0.95 (2H, m), 0.86-0.82 (2H, m). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated

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

実験手順: Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2. A solution of 2-(benzyloxy)-5-fluorobenzonitrile (148 g, 651 mmol) in methanol (2.34 L) was added slowly under N2. The air of the flask was removed by vacuum and the flask was charged with H2 (balloon) three times. The mixture was stirred at room temperature for 1 hour. The above process was repeated two more times to push the reaction to completion. The mixture was stirred at room temperature for another 2 hours. The mixture was filtered through a Celite pad under N2 and washed with EtOAc (150 mL×2). The palladium waste was rinsed with water (50 mL) and discarded. The filtrates were concentrated to give (94.6 g, 106%) of the desired compound as a yellow solid. MS (APCI−) m/z 137 (M−1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (br, 1H), 7.58 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.43 (m, 1H), 6.91-7.03 (dd, 1H J=4.5 Hz, J=9.2 Hz). Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2 The air of the flask was removed by vacuum the flask was charged with H2 (balloon) three times the reaction to completion The mixture was stirred at room temperature for another 2 hours The mixture was filtered through a Celite pad under N2 washed with EtOAc (150 mL×2) The palladium waste was rinsed with water (50 mL) The filtrates were concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer and temperature probe, a suspension of sodium hydride (74 g, 1.82 mol) in DMF (1.95 L) was added benzyl alcohol (142 g, 1.3 mol) through a dropping funnel slowly over 30 minutes in an ice bath under nitrogen. The mixture was stirred in an ice bath (0° C.) for 120 minutes, a solution of 2,5-difluorobenzonitrile (180 g, 1.3 mol) in DMF (650 mL) was added through a dropping funnel over 35 minutes. The resulting mixture was warmed up to room temperature. After 2 hours, the mixture was cooled in an ice bath (4° C.) and quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3). The slurry was stirred at room temperature overnight and the precipitate was filtered and washed with water (650 mL×3). The solid was dried in vacuum for 2 days to give 292 g (99.3%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.5-7.76 (m, 1H), 7.35-7.48 (m, 6H), 5.28 (s, 2H). In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer The resulting mixture was warmed up to room temperature After 2 hours the mixture was cooled in an ice bath (4° C.) quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3) The slurry was stirred at room temperature overnight the precipitate was filtered washed with water (650 mL×3) The solid was dried in vacuum for 2 days

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

実験手順: Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2. A solution of 2-(benzyloxy)-5-fluorobenzonitrile (148 g, 651 mmol) in methanol (2.34 L) was added slowly under N2. The air of the flask was removed by vacuum and the flask was charged with H2 (balloon) three times. The mixture was stirred at room temperature for 1 hour. The above process was repeated two more times to push the reaction to completion. The mixture was stirred at room temperature for another 2 hours. The mixture was filtered through a Celite pad under N2 and washed with EtOAc (150 mL×2). The palladium waste was rinsed with water (50 mL) and discarded. The filtrates were concentrated to give (94.6 g, 106%) of the desired compound as a yellow solid. MS (APCI-) m/z 137 (M−1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (br, 1H), 7.58 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.43 (m, 1H), 6.91-7.03 (dd, 1H J=4.5 Hz, J=9.2 Hz). Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2 The air of the flask was removed by vacuum the flask was charged with H2 (balloon) three times the reaction to completion The mixture was stirred at room temperature for another 2 hours The mixture was filtered through a Celite pad under N2 washed with EtOAc (150 mL×2) The palladium waste was rinsed with water (50 mL) The filtrates were concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer and temperature probe, a suspension of sodium hydride (74 g, 1.82 mol) in DMF (1.95 L) was added benzyl alcohol (142 g, 1.3 mol) through a dropping funnel slowly over 30 minutes in an ice bath under nitrogen. The mixture was stirred in an ice bath (0° C.) for 120 minutes, a solution of 2,5-difluorobenzonitrile (180 g, 1.3 mol) in DMF (650 mL) was added through a dropping funnel over 35 minutes. The resulting mixture was warmed up to room temperature. After 2 hours, the mixture was cooled in an ice bath (4° C.) and quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3). The slurry was stirred at room temperature overnight and the precipitate was filtered and washed with water (650 mL×3). The solid was dried in vacuum for 2 days to give 292 g (99.3%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.5-7.76 (m, 1H), 7.35-7.48 (m, 6H), 5.28 (s, 2H). In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer The resulting mixture was warmed up to room temperature After 2 hours the mixture was cooled in an ice bath (4° C.) quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3) The slurry was stirred at room temperature overnight the precipitate was filtered washed with water (650 mL×3) The solid was dried in vacuum for 2 days

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). warmed to room temperature over 1.5 h the mixture was stirred for 30 min The reaction was quenched with 1 M HCl (400 ml) the aqueous layer was separated The diethyl ether layer was further extracted into 1M HCl (2×200 mL) The combined aqueous layers were cooled in an ice bath The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) The combined filtrates were separated the aqueous layer further extracted into dichloromethane (2×200 mL) The combined organics were dried (MgSO4) evaporated residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol) The basic fractions were evaporated