达格列净杂质68

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield). was added over about 30 seconds The reaction was warmed was stirred for 17 hours was added over about 1 minutes the biphasic solution was stirred at ambient for 45 minutes The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL) The washed extract was concentrated on a rotary evaporator to about one half of its original volume was diluted with water (70 mL) Further concentration in vacuo at 45° C. formed which to cool to ambient while stirring After about 30 minutes at ambient, the suspended solids were isolated by filtration washed with water (30 mL) were dried in vacuo at 45° C After about 2.5 hours

反应条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H). To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 0° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (20 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was dissolved in absolute ethanol (45 mL) refluxed with mechanical stirring (100 RPM) cooled to 0° C After stirring for another 16 h at 0˜5° C. the mixture was filtered the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL) dried under vacuum at 40° C. for 12 h

反应条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H). To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 0° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (20 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was dissolved in absolute ethanol (45 mL) refluxed with mechanical stirring (100 RPM) cooled to 0° C After stirring for another 16 h at 0˜5° C. the mixture was filtered the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL) dried under vacuum at 40° C. for 12 h

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl) (4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield). was added over about 30 seconds The reaction was warmed was stirred for 17 hours was added over about 1 minutes the biphasic solution was stirred at ambient for 45 minutes The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL) The washed extract was concentrated on a rotary evaporator to about one half of its original volume was diluted with water (70 mL) Further concentration in vacuo at 45° C. formed which to cool to ambient while stirring After about 30 minutes at ambient, the suspended solids were isolated by filtration washed with water (30 mL) were dried in vacuo at 45° C After about 2.5 hours

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield). was added over about 30 seconds The reaction was warmed was stirred for 17 hours was added over about 1 minutes the biphasic solution was stirred at ambient for 45 minutes The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL) The washed extract was concentrated on a rotary evaporator to about one half of its original volume was diluted with water (70 mL) Further concentration in vacuo at 45° C. formed which to cool to ambient while stirring After about 30 minutes at ambient, the suspended solids were isolated by filtration washed with water (30 mL) were dried in vacuo at 45° C After about 2.5 hours

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield). was added over about 30 seconds The reaction was warmed was stirred for 17 hours was added over about 1 minutes the biphasic solution was stirred at ambient for 45 minutes The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL) The washed extract was concentrated on a rotary evaporator to about one half of its original volume was diluted with water (70 mL) Further concentration in vacuo at 45° C. formed which to cool to ambient while stirring After about 30 minutes at ambient, the suspended solids were isolated by filtration washed with water (30 mL) were dried in vacuo at 45° C After about 2.5 hours

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield). was added over about 30 seconds The reaction was warmed was stirred for 17 hours was added over about 1 minutes the biphasic solution was stirred at ambient for 45 minutes The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL) The washed extract was concentrated on a rotary evaporator to about one half of its original volume was diluted with water (70 mL) Further concentration in vacuo at 45° C. formed which to cool to ambient while stirring After about 30 minutes at ambient, the suspended solids were isolated by filtration washed with water (30 mL) were dried in vacuo at 45° C After about 2.5 hours

反应条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H). To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 0° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (20 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was dissolved in absolute ethanol (45 mL) refluxed with mechanical stirring (100 RPM) cooled to 0° C After stirring for another 16 h at 0˜5° C. the mixture was filtered the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL) dried under vacuum at 40° C. for 12 h