4-氯-3-氟苯甲醚

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated

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

实验步骤: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried The solvent was removed in vacuo The crude was purified by flash column chromatography

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

实验步骤: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried The solvent was removed in vacuo The crude was purified by flash column chromatography

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

实验步骤: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). to stir for overnight at RT was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried

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

实验步骤: Charged Tetrahydrofuran (8.35 L) into a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe under N2 atmosphere. Charged 4-Chloro-3-fluoroanisole (1000 g) to a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe. Cooled the reaction mass to −60° C. to −70° C. Added n-Butyl Lithium in hexanes (30%, 1.42 kg) in to reaction mass through canula under nitrogen atmosphere slowly, while maintaining the temperature of the reaction mass below −60° C. Maintained the reaction at below −60° C. for 2 h. Meanwhile Iodine solution prepared by dissolving Iodine (2.405 kg) in Tetrahydrofuran (2.4 L) at 25-28° C. Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse. Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C. Removed cooling bath and allowed to attain −5° C. to 0° C. Submitted the IPC sample when it reaches −5° C. to 0° C.1. A sample was removed at −2 h and checked by HPLC-97.06 AP; Int-01-0.59 AP. Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C. Allowed RM to warm to RT. Transfer resulting biphasic mixture into separating funnel, rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask. Removed and retain bottom aqueous phase for further extraction. Concentrated the organic layer. Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1). Combined all organic phases, Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1). Washed organic phases with DM water (5.7 L; 5.0-6.0 Vol wrt Int-1). Concentrated the organic layer2 on rotovap at 45-50° C. completely. Purification: Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01). Warmed to 55° C. to dissolve all solid. Rotate the above mass in rotavapor flask at 55° C. for 10 min. Cooled to ambient temperature. Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) and add rinse into reactor. Added water (1 L; 1.0-1.2 vol wrt Int-01) in to reactor with stirring. Stirred the resulting slurry for 15 min. Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min. Stirred the above mass at ambient temperature for 15 min. Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01), and collected the rinse in same container. Filtered the solid. Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01), filtered the rinse. Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01). Suck dried for 2 h, then dried at 55° C. in VTD for 15 h. Unload the material. (LOD should be less than 1%). Wt: 1533 g (85.9% yield). Description (color and appearance): Off White crystalline solid. HPLC RT Time 4.897 min Under following conditions: Detector: 210 nm; Injection volume 5.00 μL; Run Time 15 min; Column. YMC UltraHT Pro C18 (50 mm×3.0 mm), 2.0μ; Mobile Phase A—0.05% TFA in MillQ Water; Mobile Phase B—0.05% TFA in Acetonitrile; Flow: 1.0 mL/min; Column Oven—40° C.; Time (min)—0 05 10 12 15; B Conc.—10 90 90 10 10. NMR: (1H NMR, 400 MHz, dmso-d6) δ 7.58 (t, 8.8 Hz, 1H), 6.89 (m, 1H), 3.87 (s, 3H). equipped with a mechanical stirrer, an addition funnel Cooled the reaction mass to −60° C. to −70° C while maintaining the temperature of the reaction mass below −60° C Maintained the reaction at below −60° C. for 2 h Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C Removed cooling bath to attain −5° C. to 0° C reaches −5° C. to 0° C A sample was removed at −2 h Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C Transfer resulting biphasic mixture into separating funnel rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask Removed for further extraction Concentrated the organic layer Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1) Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1) Concentrated the organic layer2 on rotovap at 45-50° C. completely Purification Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01) Warmed to 55° C. to dissolve all solid Cooled to ambient temperature Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) add rinse into reactor Stirred the resulting slurry for 15 min Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min Stirred the above mass at ambient temperature for 15 min Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01) collected the rinse in same container Filtered the solid Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01) filtered the rinse Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01) Suck dried for 2 h dried at 55° C. in VTD for 15 h HPLC RT Time 4.897 min Time 15 min Column Oven—40° C.

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

实验步骤: Charged Tetrahydrofuran (8.35 L) into a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe under N2 atmosphere. Charged 4-Chloro-3-fluoroanisole (1000 g) to a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe. Cooled the reaction mass to −60° C. to −70° C. Added n-Butyl Lithium in hexanes (30%, 1.42 kg) in to reaction mass through canula under nitrogen atmosphere slowly, while maintaining the temperature of the reaction mass below −60° C. Maintained the reaction at below −60° C. for 2 h. Meanwhile Iodine solution prepared by dissolving Iodine (2.405 kg) in Tetrahydrofuran (2.4 L) at 25-28° C. Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse. Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C. Removed cooling bath and allowed to attain −5° C. to 0° C. Submitted the IPC sample when it reaches −5° C. to 0° C.1. A sample was removed at −2 h and checked by HPLC-97.06 AP; Int-01-0.59 AP. Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C. Allowed RM to warm to RT. Transfer resulting biphasic mixture into separating funnel, rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask. Removed and retain bottom aqueous phase for further extraction. Concentrated the organic layer. Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1). Combined all organic phases, Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1). Washed organic phases with DM water (5.7 L; 5.0-6.0 Vol wrt Int-1). Concentrated the organic layer2 on rotovap at 45-50° C. completely. Purification: Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01). Warmed to 55° C. to dissolve all solid. Rotate the above mass in rotavapor flask at 55° C. for 10 min. Cooled to ambient temperature. Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) and add rinse into reactor. Added water (1 L; 1.0-1.2 vol wrt Int-01) in to reactor with stirring. Stirred the resulting slurry for 15 min. Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min. Stirred the above mass at ambient temperature for 15 min. Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01), and collected the rinse in same container. Filtered the solid. Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01), filtered the rinse. Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01). Suck dried for 2 h, then dried at 55° C. in VTD for 15 h. Unload the material. (LOD should be less than 1%). Wt: 1533 g (85.9% yield). Description (color and appearance): Off White crystalline solid. HPLC RT Time 4.897 min Under following conditions: Detector: 210 nm; Injection volume 5.00 μL; Run Time 15 min; Column. YMC UltraHT Pro C18 (50 mm×3.0 mm), 2.0μ; Mobile Phase A—0.05% TFA in MillQ Water; Mobile Phase B—0.05% TFA in Acetonitrile; Flow: 1.0 mL/min; Column Oven—40° C.; Time (min)—0 05 10 12 15; B Conc.—10 90 90 10 10. NMR: (1H NMR, 400 MHz, dmso-d6) δ 7.58 (t, 8.8 Hz, 1H), 6.89 (m, 1H), 3.87 (s, 3H). equipped with a mechanical stirrer, an addition funnel Cooled the reaction mass to −60° C. to −70° C while maintaining the temperature of the reaction mass below −60° C Maintained the reaction at below −60° C. for 2 h Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C Removed cooling bath to attain −5° C. to 0° C reaches −5° C. to 0° C A sample was removed at −2 h Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C Transfer resulting biphasic mixture into separating funnel rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask Removed for further extraction Concentrated the organic layer Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1) Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1) Concentrated the organic layer2 on rotovap at 45-50° C. completely Purification Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01) Warmed to 55° C. to dissolve all solid Cooled to ambient temperature Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) add rinse into reactor Stirred the resulting slurry for 15 min Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min Stirred the above mass at ambient temperature for 15 min Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01) collected the rinse in same container Filtered the solid Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01) filtered the rinse Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01) Suck dried for 2 h dried at 55° C. in VTD for 15 h HPLC RT Time 4.897 min Time 15 min Column Oven—40° C.

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

实验步骤: 1-Chloro-2-fluoro-4-methoxybenzene was converted to 1-chloro-2-fluoro-3-iodo-4-methoxybenzene (see G. L. Grunewald et al., J. Med. Chem. 1986, 29, 1972-1982). 1-Chloro-2-fluoro-3-iodo-4-methoxybenzene was treated with methyl difluoro(fluorosulfonyl)acetate in the presence of copper iodide (A. Khilevich et al., U.S. Pat. Appl. Publ. 2010, US 20100016373) to provide 1-chloro-2-fluoro-4-methoxy-3-(trifluoromethyl)benzene. 4-Chloro-3-fluoro-2-(trifluoromethyl)phenol was then obtained by de-methylation using boron trichloride.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated

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

实验步骤: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried The solvent was removed in vacuo The crude was purified by flash column chromatography

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

实验步骤: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). to stir for overnight at RT was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried

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

实验步骤: Charged Tetrahydrofuran (8.35 L) into a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe under N2 atmosphere. Charged 4-Chloro-3-fluoroanisole (1000 g) to a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe. Cooled the reaction mass to −60° C. to −70° C. Added n-Butyl Lithium in hexanes (30%, 1.42 kg) in to reaction mass through canula under nitrogen atmosphere slowly, while maintaining the temperature of the reaction mass below −60° C. Maintained the reaction at below −60° C. for 2 h. Meanwhile Iodine solution prepared by dissolving Iodine (2.405 kg) in Tetrahydrofuran (2.4 L) at 25-28° C. Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse. Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C. Removed cooling bath and allowed to attain −5° C. to 0° C. Submitted the IPC sample when it reaches −5° C. to 0° C.1. A sample was removed at −2 h and checked by HPLC-97.06 AP; Int-01-0.59 AP. Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C. Allowed RM to warm to RT. Transfer resulting biphasic mixture into separating funnel, rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask. Removed and retain bottom aqueous phase for further extraction. Concentrated the organic layer. Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1). Combined all organic phases, Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1). Washed organic phases with DM water (5.7 L; 5.0-6.0 Vol wrt Int-1). Concentrated the organic layer2 on rotovap at 45-50° C. completely. Purification: Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01). Warmed to 55° C. to dissolve all solid. Rotate the above mass in rotavapor flask at 55° C. for 10 min. Cooled to ambient temperature. Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) and add rinse into reactor. Added water (1 L; 1.0-1.2 vol wrt Int-01) in to reactor with stirring. Stirred the resulting slurry for 15 min. Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min. Stirred the above mass at ambient temperature for 15 min. Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01), and collected the rinse in same container. Filtered the solid. Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01), filtered the rinse. Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01). Suck dried for 2 h, then dried at 55° C. in VTD for 15 h. Unload the material. (LOD should be less than 1%). Wt: 1533 g (85.9% yield). Description (color and appearance): Off White crystalline solid. HPLC RT Time 4.897 min Under following conditions: Detector: 210 nm; Injection volume 5.00 μL; Run Time 15 min; Column. YMC UltraHT Pro C18 (50 mm×3.0 mm), 2.0μ; Mobile Phase A—0.05% TFA in MillQ Water; Mobile Phase B—0.05% TFA in Acetonitrile; Flow: 1.0 mL/min; Column Oven—40° C.; Time (min)—0 05 10 12 15; B Conc.—10 90 90 10 10. NMR: (1H NMR, 400 MHz, dmso-d6) δ 7.58 (t, 8.8 Hz, 1H), 6.89 (m, 1H), 3.87 (s, 3H). equipped with a mechanical stirrer, an addition funnel Cooled the reaction mass to −60° C. to −70° C while maintaining the temperature of the reaction mass below −60° C Maintained the reaction at below −60° C. for 2 h Transferred the Iodine solution in step #6 into a clean addition funnel with THF (500 mL) rinse Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <−60° C Removed cooling bath to attain −5° C. to 0° C reaches −5° C. to 0° C A sample was removed at −2 h Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10° C Transfer resulting biphasic mixture into separating funnel rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask Removed for further extraction Concentrated the organic layer Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1) Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1) Concentrated the organic layer2 on rotovap at 45-50° C. completely Purification Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01) Warmed to 55° C. to dissolve all solid Cooled to ambient temperature Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) add rinse into reactor Stirred the resulting slurry for 15 min Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min Stirred the above mass at ambient temperature for 15 min Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01) collected the rinse in same container Filtered the solid Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01) filtered the rinse Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01) Suck dried for 2 h dried at 55° C. in VTD for 15 h HPLC RT Time 4.897 min Time 15 min Column Oven—40° C.