methyl 3-amino-5-fluorobenzoate

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: 3-bromo-5-fluorobenzoic acid (6.12 g, 33.1 mmol) was dissolved in MeOH (10 mL) and cooled in ice-water bath and toluene (50 mL) and then TMS-diazomethane (19.84 mL, 39.7 mmol) was added dropwise. Reaction mixture was allowed to return to room temperature for 1 h and concentrated in vacuo and the residue dissolved in DCM/Ether and filtered through a short plug of silica and the filtrate evaporated in vacuo to afford the desired product which was then dissolved in MeOH (60 mL) and Pd/C 10 wt % 3.3 g was added and the mixture evacuated and stirred under 1 atm of hydrogen overnight and LCMS indicated desired product next morning. The reaction mixture was filtered through Celite and the filtrate was concnetrated in vacuo and the residue azeotroped with toluene twice and taken to the next step as such (99%). LCMS (m/z): 211.1 (MH+), 0.55 min. Reaction mixture concentrated in vacuo the residue dissolved in DCM/Ether filtered through a short plug of silica the filtrate evaporated in vacuo

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

実験手順: 3-bromo-5-fluorobenzoic acid (6.12 g, 33.1 mmol) was dissolved in MeOH (10 mL) and cooled in ice-water bath and toluene (50 mL) and then TMS-diazomethane (19.84 mL, 39.7 mmol) was added dropwise. Reaction mixture was allowed to return to room temperature for 1 h and concentrated in vacuo and the residue dissolved in DCM/Ether and filtered through a short plug of silica and the filtrate evaporated in vacuo to afford the desired product which was then dissolved in MeOH (60 mL) and Pd/C 10 wt % 3.3 g was added and the mixture evacuated and stirred under 1 atm of hydrogen overnight and LCMS indicated desired product next morning. The reaction mixture was filtered through Celite and the filtrate was concnetrated in vacuo and the residue azeotroped with toluene twice and taken to the next step as such (99%). LCMS (m/z): 211.1 (MH+), 0.55 min. Reaction mixture concentrated in vacuo the residue dissolved in DCM/Ether filtered through a short plug of silica the filtrate evaporated in vacuo

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of methyl 2-oxocycloheptanecarboxylate (0.34 g, 2 mmol), methyl 3-amino-5-fluorobenzoate (0.33 g, 2 mmol), polyphosphoric acid (4.0 g) and dioxane (5 mL) was heated at 130° C. for 5 hours. After cooling to room temperature, the solution was diluted with water (100 mL), and NaOAc.3H2O (7.3 g) was added. Then the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (20 mL) and SOCl2 (10 mL) was added, the mixture was stirred at reflux for 5 hours, concentrated and treated with water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layer was separated, concentrated and the residue was chromatographed to give the crude product (0.62 g). MS (ESI) m/e [M+1]+290.0. After cooling to room temperature was added Then the resulting precipitate was collected by filtration dried SOCl2 (10 mL) was added at reflux for 5 hours concentrated treated with water (50 mL) extracted with ethyl acetate (3×50 mL) The organic layer was separated concentrated the residue was chromatographed

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

実験手順: To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5%, 50% water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88%) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=1.8 Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H), 6.58 (m, 1H), 3.82 (s, 3H). Then the mixture was filtered washed with MeOH (10 mL) The filtrate was concentrated recrystallized with MeOH (2.5 mL)

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

実験手順: To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5%, 50% water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88%) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=1.8 Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H), 6.58 (m, 1H), 3.82 (s, 3H). Then the mixture was filtered washed with MeOH (10 mL) The filtrate was concentrated recrystallized with MeOH (2.5 mL)

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 mixture solution of 3-amino-5-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+]336.0 & 338.0. to reflux for 12 hours The solvent was removed in vacuo the residue was washed with ether

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

実験手順: To a stirred solution of 3-amino-5-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. Then the mixture solution was refluxed for 12 hours Then the reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (500 mL) washed with saturated aqueous sodium bicarbonate solution (3×100 mL) dried over anhydrous sodium sulfate concentrated in vacuo

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

実験手順: A mixture solution of 3-amino-5-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0. to reflux for 12 hours The solvent was removed in vacuo the residue was washed with ether

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

実験手順: To a stirred solution of 3-amino-5-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. Then the mixture solution was refluxed for 12 hours Then the reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (500 mL) washed with saturated aqueous sodium bicarbonate solution (3×100 mL) dried over anhydrous sodium sulfate concentrated in vacuo

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

実験手順: 3-bromo-5-fluorobenzoic acid (6.12 g, 33.1 mmol) was dissolved in MeOH (10 mL) and cooled in ice-water bath and toluene (50 mL) and then TMS-diazomethane (19.84 mL, 39.7 mmol) was added dropwise. Reaction mixture was allowed to return to room temperature for 1 h and concentrated in vacuo and the residue dissolved in DCM/Ether and filtered through a short plug of silica and the filtrate evaporated in vacuo to afford the desired product which was then dissolved in MeOH (60 mL) and Pd/C 10 wt % 3.3 g was added and the mixture evacuated and stirred under 1 atm of hydrogen overnight and LCMS indicated desired product next morning. The reaction mixture was filtered through Celite and the filtrate was concnetrated in vacuo and the residue azeotroped with toluene twice and taken to the next step as such (99%). LCMS (m/z): 211.1 (MH+), 0.55 min. Reaction mixture concentrated in vacuo the residue dissolved in DCM/Ether filtered through a short plug of silica the filtrate evaporated in vacuo