Methyl 3-aMino-5-fluorobenzoate

Uses

Synthesis

1342063-52-8

884497-46-5

General procedure for the synthesis of methyl 3-amino-5-fluorobenzoate from methyl 3-amino-2-bromo-5-fluorobenzoate: 1. 500 mL of concentrated sulfuric acid followed by 40 mL of fuming nitric acid was added to a 3-liter round-bottomed flask and mixed with gentle stirring. 2. 60 g (219 mmol) of 2-bromo-5-fluorobenzoic acid was added to the reaction mixture in 5 g batches over 90 min at 5-10 °C. After addition, stirring was continued for 60 minutes to ensure complete reaction. 3. The reaction mixture was poured into 1 liter of ice-water mixture and extracted with ethyl acetate (3 x 600 mL). The organic layers were combined, dried with magnesium sulfate and concentrated under reduced pressure to give a yellow solid. 4. The solid was suspended in hexane, stirred for 30 min and filtered, the solid was collected to give 2-bromo-5-fluoro-3-nitrobenzoic acid (35 g, 49% yield). 5. To a 400 mL methanolic solution of 35 g of 2-bromo-5-fluoro-3-nitrobenzoic acid was added dropwise 40 mL of thionyl chloride at 10-15 °C. The reaction mixture was then stirred at 65°C for 1 hour. 6. After cooling to room temperature, the solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography using a gradient elution with a hexane solution of 0-100% ethyl acetate to afford methyl 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 84% yield). 7. 20 g (278 mmol) of methyl 2-bromo-5-fluoro-3-nitrobenzoate was dissolved in a mixed solution of 200 mL of ethanol and 200 mL of acetic acid, and 25 g (55 mmol) of iron powder was added. The reaction was heated to 85°C for 1 hour with vigorous stirring. 8. After cooling, the reaction mixture was diluted with water, the pH was adjusted to 8 with sodium bicarbonate, and extracted with ethyl acetate (3 x 450 mL). The organic layers were combined, washed with 500 mL of brine, dried over magnesium sulfate, filtered and evaporated under vacuum. 9. The residue was purified by fast column chromatography (silica gel) to afford methyl 3-amino-2-bromo-5-fluorobenzoate (15.6 g, 87% yield) as a red oil. 10. To an 80 mL methanol solution of 2.48 g (10 mmol) of methyl 3-amino-2-bromo-5-fluorobenzoate was added 0.5 g of 5% Pd/C (50% water moistened), and stirred at atmospheric pressure under a hydrogen atmosphere for about 6 hours. 11. The reaction was completed by filtration and the catalyst was washed with 10 mL of methanol. The filtrate was concentrated and recrystallized from 2.5 mL of methanol to give methyl 3-amino-5-fluorobenzoate (1.48 g, 88% yield) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=1.8Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H), 6.58 (m, 1H), 3.82 (s, 3H).

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