反应详情

To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216(M+3)+.

1. additionwas added drop-wise at −5˜0° C. in a period of about 1.5 hrs
2. additionAfter the addition
3. additionThe mixture was poured into crash ice
4. stirringwith vigorous stirring
5. filtrationthe precipitate was collected by filtration
6. dissolutionThe precipitate was dissolved in EtOAc
7. washwashed with brine
8. dry with materialdried over anhydrous Na2SO4
9. concentrationconcentrated