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With sulfuric acid; potassium nitrate; at 0 - 20℃; for 3.16667h;
Potassium nitrate (11.54 g, 114 mmol) was added portionwise to a solution of 2-bromo-4-fluorobenzoic acid (25 g, 114 mmol) in sulfuric Acid (228 mL) <n="138"/>at 0 0C over 10 min. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was poured onto ice. The resulting precipitate was washed with water and dried in vacuo to yield a mixture of 21A and 2-Br-4-F-6-nitrobenzoic acid (9: 1) as a white solid (19.5 g). 7 g of this solid was purified by prep HPLC (0.1% TFA, H2OMeOH, 35% to 60%) to yield 21A (5.6 g, 21.21 mmol) as a white solid. MS (ESI) m/z 262.1/264.1 (M-H)". 1H NMR (400 MHz, CD3OD) delta ppm 7.91 (d, J=10.44 Hz, 1 H) 8.61 (d, J=8.25 Hz, 1 H).;
With sulfuric acid; nitric acid; In water; at 20℃; for 1h;Cooling with ice;
Fuming nitric acid (4 ml, 45.60 mmol) was added dropwise to a mixed solution of 2-bromo-4-fluorobenzoic acid (10 g, 45.66 mmol) and concentrated sulfuric acid (34 ml) under ice-cooling.The reaction system was dripped into ice water and stirred rapidly for 1 hour. The solid was collected by filtration, washed with ice water and dried to give 10.40 g of a white solid (10.4 g), which was washed with water and evaporated to dryness to give a white solid Solid, yield 86%.
73%
With sulfuric acid; nitric acid; at 0 - 20℃; for 3h;
Fuming 113 nitric acid (8 mL) was added dropwise to a mixture of 114 2-bromo-4-fluorobenzoic acid (20 g, 91.2 mmol) in 115 concentrated sulfuric acid (68 mL) at 0 C. After stirring at room temperature for 3 h, the mixture was poured into ice water and stirred rapidly for 1 hour. The solid was collected by filtration, washed with water and dried to give 116 compound 16A (17.59 g, 73% yield) as a white solid: 1H NMR (400 MHz, CDCl3) delta 8.81 (d, J=8 Hz, 1H), 7.73 (d, J=10 Hz, 1H).
52%
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 3h;
To a solution of 183 (25 g, 114 mmol) in sulfuric acid (228 mL) is added potassium nitrate (11.5 g, 114 mmol) at 0 C over 10 minutes. After stirring at room temperature for 3 hours, the mixture is poured onto ice and the solid is collected by filtration, washed with water, dned,and purified by prep-HPLC (water/MeOH with 0.1% TFA, 35% to 60%) to give 184 as a white solid (5.6 g, 52% yield). (MS: [M+Hf 265.2)
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 3.16667h;
Intermediate 7: 6-amino-5-fluoroisoindolin-l-one; <n="94"/>Intermediate 7A:; [00206] Potassium nitrate (11.54 g, 114 mmol) was added portionwise to a solution of 2-bromo-4-fluorobenzoic acid (25 g, 114 mmol) in sulfuric acid (228 mL) at 0 0C over 10 min. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was poured onto ice. The resulting precipitate was washed with water and dried in vacuo to yield a mixture of Intermediate 7 A and 2-Br-4-F-6- nitrobenzoic acid (9: 1) as a white solid (19.5 g). 7 g of this solid was purified by prep HPLC (0.1% TFA, H2OMeOH, 35% to 60%) to yield Intermediate 7A (5.6 g, 21.21 mmol) as a white solid. MS (ESI) m/z 262.1/264.1 (M-H)".
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 3h;
To a cooled solution of 2-bromo-4-fluorobenzoic acid (5.00 g, 22.83 mmol) in sulfuric acid (42.5 mL) at 0 C. was added potassium nitrate portionwise (2.31 g, 22.83 mmol) over 5 minutes with the resulting solution stirred at ambient temperature for 3 h. After this time the reaction mixture was poured onto ice and the resultant precipitate was filtered, washing with water and dried in vacuo for 60 h to afford a mixture of regioisomers favouring the title compound (4:1; 5.03 g, 70% yield) as an off-white solid. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 8.51 (d, J=8.0 Hz, 1H), 8.17 (d, J=10.9 Hz, 1H). LCMS (Analytical Method A): Rt=0.91 min; MS (ESIPos) m/z=261.8/263.8 (M-H)-, Br isotope pattern.
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