methyl 2-(5-chloro-2-methoxyphenyl)acetate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742,1250, 1150, 1028; 1H NMR (300 MHz, CDCl3)δ 3.56 (2H, s), 3.66 (3H, s), 3.76 (3 H, s), 8.75 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=2.5 Hz), 7.17 (1H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+). was heated to reflux under nitrogen for 2 hours to cool the excess dimethyl sulfate was quenched with Et3N (1 mL) filtered The filtrate was rotary evaporated extracted with ether washed with satd NaHCO3, water, brine and then dried (Na2SO4) Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo

反応条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet, thermocouple and reflux condenser, was vacuum/argon purged. The flask was charged with the product obtained in Step A (345.0 g, 1.72 mol), anhydrous potassium carbonate (285 g, 2.06 mol) and anhydrous acetonitrile (1.7 L). To the resultant suspension was added dimethyl sulfate (200 mL, 2.11 mol) over 5 minutes with stirring and then heated to reflux at about 82° C. for 1.5 h to complete the esterification. The reaction mixture was cooled to room temperature and the excess dimethyl sulfate was quenched with triethylamine (70 mL). The resultant precipitate was filtered and washed with ethyl acetate (2 L) and the combined filtrate was concentrated on a rotary evaporator to afford a residue. This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L). The organic layer was separated, washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) and dried over magnesium sulfate. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil. This residual oil was distilled under vacuum (170° C. at about 25 mm Hg) to afford 310 g (about 85% yield, 97% by HPLC) of the title compound as a viscous pale yellow oil. A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet thermocouple and reflux condenser purged heated The reaction mixture was cooled to room temperature the excess dimethyl sulfate was quenched with triethylamine (70 mL) The resultant precipitate was filtered washed with ethyl acetate (2 L) the combined filtrate was concentrated on a rotary evaporator to afford a residue This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L) The organic layer was separated washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) dried over magnesium sulfate The solution was filtered the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil This residual oil was distilled under vacuum (170° C. at about 25 mm Hg)

反応条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet, thermocouple and reflux condenser, was vacuum/argon purged. The flask was charged with the product obtained in Step A (345.0 g, 1.72 mol), anhydrous potassium carbonate (285 g, 2.06 mol) and anhydrous acetonitrile (1.7 L). To the resultant suspension was added dimethyl sulfate (200 mL, 2.11 mol) over 5 minutes with stirring and then heated to reflux at about 82° C. for 1.5 h to complete the esterification. The reaction mixture was cooled to room temperature and the excess dimethyl sulfate was quenched with triethylamine (70 mL). The resultant precipitate was filtered and washed with ethyl acetate (2 L) and the combined filtrate was concentrated on a rotary evaporator to afford a residue. This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L). The organic layer was separated, washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) and dried over magnesium sulfate. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil. This residual oil was distilled under vacuum (170° C. at about 25 mm Hg) to afford 310 g (about 85% yield, 97% by HPLC) of the title compound as a viscous pale yellow oil. A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet thermocouple and reflux condenser purged heated The reaction mixture was cooled to room temperature the excess dimethyl sulfate was quenched with triethylamine (70 mL) The resultant precipitate was filtered washed with ethyl acetate (2 L) the combined filtrate was concentrated on a rotary evaporator to afford a residue This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L) The organic layer was separated washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) dried over magnesium sulfate The solution was filtered the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil This residual oil was distilled under vacuum (170° C. at about 25 mm Hg)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A four-necked 12-L round-bottomed flask, equipped with a septa, mechanical stirrer, argon inlet, thermocouple and 2-L addition funnel capped with a septa, was argon purged. The 5-chloro-2-methoxyphenylacetic acid, methyl ester from Example 1 (309.15 g, 1.44 mol) and 4-fluoro-3-nitro-benzotrifluoride (207.5 mL, 310.0 g, 1.48 mol) were transferred into the flask via a cannula and dissolved in anhydrous THF (750 mL). The clear light yellow solution was cooled in an acetone/dry ice bath to approximately -20° C. A solution of lithium hexamethyldisilazane in THF (1.0 N, 3.16 L, 3.16 mol; dark orange-yellow in color) was transferred to the addition funnel and then added to the reaction mixture over a total of 1.5 hours. The internal temperature of the reaction mixture was maintained between -26° and -16° C. HPLC analysis after 10 minutes showed the reaction was complete. After a total of 40 minutes from the time of complete addition of lithium hexamethyldisilazane, a solution of N-fluoro-bis (phenylsulfonyl) amine (NFSi) (Accufluor198) (467.1 g, 1.48 mol, pink in color, Allied Signal, Buffalo Research Lab, 20 Peabody Street, Buffalo, N.Y.) in anhydrous THF (1.25 L) was cannulated into the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at about -10° C. during the exothermic addition of the N-fluoro-bis(phenylsulfonyl)amine (Accufluor198) solution. The cooling bath was removed and the reaction mixture was allowed to warm to about 0° C. over about 1 hour, and HPLC analysis showed the reaction was complete. The reaction mixture was quenched with acetic acid (200 mL) resulting in an exotherm to 40° C., precipitation of the N-fluorobenzenesulfonide (Accufluor198) by-product and a color change from dark reddish-brown to orange. The mixture was diluted with water (4 L) and extracted with ethyl acetate (2×4 L). The combined organic layer was washed with 10% sodium carbonate (4×4 L), 50% saturated sodium chloride solution (1×4 L), 0.5 N HCI (1×4 L) and saturated sodium chloride solution (1×4 L). The first two base washes, the 50% saturated sodium chloride solution wash and the HCI wash were back-extracted with ethyl acetate (2 L) and this organic layer was washed with saturated sodium chloride solution (1 L). The combined organic layers were then concentrated under vacuum at about 35° C. on a rotary evaporator to afford a semi-solid black residue (87% by HPLC). The residual oil was azeotropically dried with ethanol (2×500 mL) to remove water and ethyl acetate before crystallization. A 5-L flask equipped with a mechanical stirrer was charged with this residue and dissolved in ethanol (1.5 L) while stirring and heating in a boiling water bath. Heptane (2.6 L) was slowly added and the hot water bath was removed. The solution was allowed to slowly cool to room temperature (over 2 hours) to crystallize the product. After stirring for 16 hours, the suspension was cooled to 0° C. and stirred for 2.5 hours. The cold suspension was filtered, washed with cold 1:1 ethanol/heptane (1 L). The solid was air dried for about 2 h and then vacuum dried to afford 478.2 g of the title compound (78.8% yield, 99.3% by HPLC) as an off-white-peach colored solid. A four-necked 12-L round-bottomed flask, equipped with a septa, mechanical stirrer, argon inlet capped with a septa purged added to the reaction mixture over a total of 1.5 hours The internal temperature of the reaction mixture was maintained between -26° and -16° C The cooling bath was removed to warm to about 0° C. over about 1 hour The reaction mixture was quenched with acetic acid (200 mL) resulting in an exotherm to 40° C. precipitation of the N-fluorobenzenesulfonide (Accufluor198) by-product The mixture was diluted with water (4 L) extracted with ethyl acetate (2×4 L) The combined organic layer was washed with 10% sodium carbonate (4×4 L), 50% saturated sodium chloride solution (1×4 L), 0.5 N HCI (1×4 L) and saturated sodium chloride solution (1×4 L) The first two base washes, the 50% saturated sodium chloride solution wash the HCI wash were back-extracted with ethyl acetate (2 L) this organic layer was washed with saturated sodium chloride solution (1 L) The combined organic layers were then concentrated under vacuum at about 35° C. on a rotary evaporator to afford a semi-solid black residue (87% by HPLC) The residual oil was azeotropically dried with ethanol (2×500 mL) to remove water and ethyl acetate before crystallization A 5-L flask equipped with a mechanical stirrer was charged with this residue dissolved in ethanol (1.5 L) heating in a boiling water bath Heptane (2.6 L) was slowly added the hot water bath was removed to slowly cool to room temperature (over 2 hours) to crystallize the product After stirring for 16 hours the suspension was cooled to 0° C. stirred for 2.5 hours The cold suspension was filtered washed with cold 1:1 ethanol/heptane (1 L) dried for about 2 h vacuum dried

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A four-necked 12-L round-bottomed flask, equipped with a septa, mechanical stirrer, argon inlet, thermocouple and 2-L addition funnel capped with a septa, was argon purged. The 5-chloro-2-methoxyphenylacetic acid, methyl ester from Example 1 (309.15 g, 1.44 mol) and 4-fluoro-3-nitro-benzotrifluoride (207.5 mL, 310.0 g, 1.48 mol) were transferred into the flask via a cannula and dissolved in anhydrous THF (750 mL). The clear light yellow solution was cooled in an acetone/dry ice bath to approximately -20° C. A solution of lithium hexamethyldisilazane in THF (1.0 N, 3.16 L, 3.16 mol; dark orange-yellow in color) was transferred to the addition funnel and then added to the reaction mixture over a total of 1.5 hours. The internal temperature of the reaction mixture was maintained between -26° and -16° C. HPLC analysis after 10 minutes showed the reaction was complete. After a total of 40 minutes from the time of complete addition of lithium hexamethyldisilazane, a solution of N-fluoro-bis (phenylsulfonyl) amine (NFSi) (Accufluor198) (467.1 g, 1.48 mol, pink in color, Allied Signal, Buffalo Research Lab, 20 Peabody Street, Buffalo, N.Y.) in anhydrous THF (1.25 L) was cannulated into the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at about -10° C. during the exothermic addition of the N-fluoro-bis(phenylsulfonyl)amine (Accufluor198) solution. The cooling bath was removed and the reaction mixture was allowed to warm to about 0° C. over about 1 hour, and HPLC analysis showed the reaction was complete. The reaction mixture was quenched with acetic acid (200 mL) resulting in an exotherm to 40° C., precipitation of the N-fluorobenzenesulfonide (Accufluor198) by-product and a color change from dark reddish-brown to orange. The mixture was diluted with water (4 L) and extracted with ethyl acetate (2×4 L). The combined organic layer was washed with 10% sodium carbonate (4×4 L), 50% saturated sodium chloride solution (1×4 L), 0.5 N HCI (1×4 L) and saturated sodium chloride solution (1×4 L). The first two base washes, the 50% saturated sodium chloride solution wash and the HCI wash were back-extracted with ethyl acetate (2 L) and this organic layer was washed with saturated sodium chloride solution (1 L). The combined organic layers were then concentrated under vacuum at about 35° C. on a rotary evaporator to afford a semi-solid black residue (87% by HPLC). The residual oil was azeotropically dried with ethanol (2×500 mL) to remove water and ethyl acetate before crystallization. A 5-L flask equipped with a mechanical stirrer was charged with this residue and dissolved in ethanol (1.5 L) while stirring and heating in a boiling water bath. Heptane (2.6 L) was slowly added and the hot water bath was removed. The solution was allowed to slowly cool to room temperature (over 2 hours) to crystallize the product. After stirring for 16 hours, the suspension was cooled to 0° C. and stirred for 2.5 hours. The cold suspension was filtered, washed with cold 1:1 ethanol/heptane (1 L). The solid was air dried for about 2 h and then vacuum dried to afford 478.2 g of the title compound (78.8% yield, 99.3% by HPLC) as an off-white-peach colored solid. A four-necked 12-L round-bottomed flask, equipped with a septa, mechanical stirrer, argon inlet capped with a septa purged added to the reaction mixture over a total of 1.5 hours The internal temperature of the reaction mixture was maintained between -26° and -16° C The cooling bath was removed to warm to about 0° C. over about 1 hour The reaction mixture was quenched with acetic acid (200 mL) resulting in an exotherm to 40° C. precipitation of the N-fluorobenzenesulfonide (Accufluor198) by-product The mixture was diluted with water (4 L) extracted with ethyl acetate (2×4 L) The combined organic layer was washed with 10% sodium carbonate (4×4 L), 50% saturated sodium chloride solution (1×4 L), 0.5 N HCI (1×4 L) and saturated sodium chloride solution (1×4 L) The first two base washes, the 50% saturated sodium chloride solution wash the HCI wash were back-extracted with ethyl acetate (2 L) this organic layer was washed with saturated sodium chloride solution (1 L) The combined organic layers were then concentrated under vacuum at about 35° C. on a rotary evaporator to afford a semi-solid black residue (87% by HPLC) The residual oil was azeotropically dried with ethanol (2×500 mL) to remove water and ethyl acetate before crystallization A 5-L flask equipped with a mechanical stirrer was charged with this residue dissolved in ethanol (1.5 L) heating in a boiling water bath Heptane (2.6 L) was slowly added the hot water bath was removed to slowly cool to room temperature (over 2 hours) to crystallize the product After stirring for 16 hours the suspension was cooled to 0° C. stirred for 2.5 hours The cold suspension was filtered washed with cold 1:1 ethanol/heptane (1 L) dried for about 2 h vacuum dried

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15° C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step. A flame dried three-necked 3-L round-bottomed flask, equipped with a septa thermocouple and addition funnel capped with a septa purged stirred until the solution while stirring over an hour The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.) The resultant slurry was stirred for 3 hours the white precipitate was collected by filtration washed with water (2 L), air dried for about 24 h vacuum dried

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15° C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step. A flame dried three-necked 3-L round-bottomed flask, equipped with a septa thermocouple and addition funnel capped with a septa purged stirred until the solution while stirring over an hour The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.) The resultant slurry was stirred for 3 hours the white precipitate was collected by filtration washed with water (2 L), air dried for about 24 h vacuum dried

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

実験手順: A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2-methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742, 1250, 1150, 1028; 1H NMR (300 MHz, CDCl3)δ 3.56 (2 H, s), 3.66 (3 H, s), 3.76 (3 H, s), 8.75 (16 H, d, J=8.6 Hz), 7.13 (1 H, d, J=2.5 Hz), 7.17 (1 H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+). was heated to reflux under nitrogen for 2 hours to cool the excess dimethyl sulfate was quenched with Et3N (1 mL) filtered The filtrate was rotary evaporated extracted with ether washed with satd NaHCO3, water, brine and then dried (Na2SO4) Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo

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

実験手順: A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742,1250, 1150, 1028; 1H NMR (300 MHz, CDCl3)δ 3.56 (2H, s), 3.66 (3H, s), 3.76 (3 H, s), 8.75 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=2.5 Hz), 7.17 (1H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+). was heated to reflux under nitrogen for 2 hours to cool the excess dimethyl sulfate was quenched with Et3N (1 mL) filtered The filtrate was rotary evaporated extracted with ether washed with satd NaHCO3, water, brine and then dried (Na2SO4) Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo

反応条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet, thermocouple and reflux condenser, was vacuum/argon purged. The flask was charged with the product obtained in Step A (345.0 g, 1.72 mol), anhydrous potassium carbonate (285 g, 2.06 mol) and anhydrous acetonitrile (1.7 L). To the resultant suspension was added dimethyl sulfate (200 mL, 2.11 mol) over 5 minutes with stirring and then heated to reflux at about 82° C. for 1.5 h to complete the esterification. The reaction mixture was cooled to room temperature and the excess dimethyl sulfate was quenched with triethylamine (70 mL). The resultant precipitate was filtered and washed with ethyl acetate (2 L) and the combined filtrate was concentrated on a rotary evaporator to afford a residue. This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L). The organic layer was separated, washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) and dried over magnesium sulfate. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil. This residual oil was distilled under vacuum (170° C. at about 25 mm Hg) to afford 310 g (about 85% yield, 97% by HPLC) of the title compound as a viscous pale yellow oil. A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet thermocouple and reflux condenser purged heated The reaction mixture was cooled to room temperature the excess dimethyl sulfate was quenched with triethylamine (70 mL) The resultant precipitate was filtered washed with ethyl acetate (2 L) the combined filtrate was concentrated on a rotary evaporator to afford a residue This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L) The organic layer was separated washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) dried over magnesium sulfate The solution was filtered the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil This residual oil was distilled under vacuum (170° C. at about 25 mm Hg)