3-溴-6-氟-2-甲氧基苯甲醛

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-bromo-6-fluoro-2-methoxybenzaldehyde (0.727 g, 3.12 mmol) and methoxylamine hydrochloride (0.260 g, 3.12 mmol) in 1,2-dimethoxyethane (4 mL) was treated with potassium carbonate (0.472 g, 3.42 mmol) and stirred at 20° C. for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. This residue was dissolved in 1,2-dimethoxyethane (4 mL), the resultant solution was treated with hydrazine (4 mL), warmed to 100° C. and stirred at that temperature for 15 h. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. This residue was triturated with ether to give the desired product (185 mg, 26%) as a gray solid. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 226.9, 229.0. The reaction mixture was filtered the filtrate was concentrated in vacuo to give a residue warmed to 100° C. stirred at that temperature for 15 h Layers were separated the organic layer was separated washed with brine dried with magnesium sulfate filtered concentrated in vacuo to give a crude residue This residue was triturated with ether

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

实验步骤: 1.6 M Solution of n-butyllithium in hexanes (3.35 mL, 5.36 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.960 mL, 6.85 mmol) in tetrahydrofuran (10 mL) at −78° C. and the resultant reaction mixture was stirred at −78° C. for 10 min. A solution of 1-bromo-4-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. N,N-dimethylformamide (0.412 mL, 5.32 mmol) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. Reaction mixture was quenched with saturated ammonium chloride, warmed to 20° C., and diluted with ether and 1M aqueous solution of HCl. Layers were separated and the aqueous layer was and re-extracted with ether. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (727 mg, 64%) as a yellow solid. LCMS calculated for C8H7BrFO2 (M+H)+: m/z=233.0, 235.0. found: 233.0, 234.8. the resultant reaction mixture the reaction mixture was stirred at −78° C. for 1 h the reaction mixture was stirred at −78° C. for 1 h Reaction mixture was quenched with saturated ammonium chloride warmed to 20° C. diluted with ether and 1M aqueous solution of HCl Layers were separated re-extracted with ether The combined organic layers were washed with brine dried with magnesium sulfate filtered concentrated in vacuo to give a crude residue Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes)

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

实验步骤: In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil. the mixture was stirred under ice- cooling for 15 minutes was then stirred at −78° C. for 8 minutes After stirring at the same temperature for 30 minutes the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil. the mixture was stirred under ice- cooling for 15 minutes was then stirred at −78° C. for 8 minutes After stirring at the same temperature for 30 minutes the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 5 g of N,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour and 10 minutes, 9.27 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1.5 hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirring at the same temperature for 25 minutes, 9 ml of acetic acid was added at the same temperature, water was added at room temperature, and the mixture was extracted with diethyl ether for three times. The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 5.65 g of the title compound as pale yellow crystals. was added dropwise After stirring at the same temperature for 1.5 hours After stirring at the same temperature for 25 minutes was added at room temperature the mixture was extracted with diethyl ether for three times The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 5 g of N,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour and 10 minutes, 9.27 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1.5 hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirring at the same temperature for 25 minutes, 9 ml of acetic acid was added at the same temperature, water was added at room temperature, and the mixture was extracted with diethyl ether for three times. The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 5.65 g of the title compound as pale yellow crystals. was added dropwise After stirring at the same temperature for 1.5 hours After stirring at the same temperature for 25 minutes was added at room temperature the mixture was extracted with diethyl ether for three times The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: To a solution of diisopropylamine (6.89 g, 9.6 mL, 68.3 mmol) in THF (100 mL) at −78° C. was added n-butyl lithium (33.5 mL of 1.6 M solution in hexane, 53.6 mmol) over 3 mins. After stirring at −78° C. for 10 mins, 2-bromo-5-fluoroanisole (10 g, 48.8 mmol) in THF (20 mL) was added dropwise over 15 mins. After completion of the addition, the mixture was stirred at −78° C. for 1 hr and then DMF (3.91 g, 4.12 mL, 53.6 mmol) was added dropwise over 3 mins and stirring was continued at −78° C. for 45 mins. Saturated NH4Cl solution was added and the mixture allowed to each room temperature. Diethyl ether and 2M HCl were added, the product was extracted into diethyl ether and the combined extracts were washed with brine, dried and evaporated. Chromatography on silica gel followed by trituration of the product with diethyl ether gave the title compound (D18) as a yellow solid (6.84 g) After completion of the addition the mixture was stirred at −78° C. for 1 hr stirring was continued at −78° C. for 45 mins allowed to each room temperature the product was extracted into diethyl ether the combined extracts were washed with brine dried evaporated

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

实验步骤: To a solution of diisopropylamine (6.89 g, 9.6 mL, 68.3 mmol) in THF (100 mL) at −78° C. was added n-butyl lithium (33.5 mL of 1.6 M solution in hexane, 53.6 mmol) over 3 mins. After stirring at −78° C. for 10 mins, 2-bromo-5-fluoroanisole (10 g, 48.8 mmol) in THF (20 mL) was added dropwise over 15 mins. After completion of the addition, the mixture was stirred at −78° C. for 1 hr and then DMF (3.91 g, 4.12 mL, 53.6 mmol) was added dropwise over 3 mins and stirring was continued at −78° C. for 45 mins. Saturated NH4Cl solution was added and the mixture allowed to each room temperature. Diethyl ether and 2M HCl were added, the product was extracted into diethyl ether and the combined extracts were washed with brine, dried and evaporated. Chromatography on silica gel followed by trituration of the product with diethyl ether gave the title compound (D18) as a yellow solid (6.84 g) After completion of the addition the mixture was stirred at −78° C. for 1 hr stirring was continued at −78° C. for 45 mins allowed to each room temperature the product was extracted into diethyl ether the combined extracts were washed with brine dried evaporated

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

实验步骤: In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil. the mixture was stirred under ice- cooling for 15 minutes was then stirred at −78° C. for 8 minutes After stirring at the same temperature for 30 minutes the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 5 g of N,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour and 10 minutes, 9.27 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1.5 hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirring at the same temperature for 25 minutes, 9 ml of acetic acid was added at the same temperature, water was added at room temperature, and the mixture was extracted with diethyl ether for three times. The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 5.65 g of the title compound as pale yellow crystals. was added dropwise After stirring at the same temperature for 1.5 hours After stirring at the same temperature for 25 minutes was added at room temperature the mixture was extracted with diethyl ether for three times The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil. the mixture was stirred under ice- cooling for 15 minutes was then stirred at −78° C. for 8 minutes After stirring at the same temperature for 30 minutes the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography

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

实验步骤: In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 5 g of N,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour and 10 minutes, 9.27 g of l-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1.5 hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirring at the same temperature for 25 minutes, 9 ml of acetic acid was added at the same temperature, water was added at room temperature, and the mixture was extracted with diethyl ether for three times. The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 5.65 g of the title compound as pale yellow crystals. was added dropwise After stirring at the same temperature for 1.5 hours After stirring at the same temperature for 25 minutes was added at room temperature the mixture was extracted with diethyl ether for three times The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography