Nitric Acid → 5-Fluoro-2-methyl-3-nitrobenzoic acid

HRID 1967953Notes

Reaction equation

HRID 1967953 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]

Participants

4

Reactant 2

HCID 944Nitric AcidHCID 1821145-Fluoro-2-methylbenzoic acid

Product 1

HCID 179850235-Fluoro-2-methyl-3-nitrobenzoic acidYield 52.1%

Reagents, catalysts & solvents 1

HCID 1118Sulfuric AcidSolvent2×

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-29d3f5f8fbc5461fbdda6ecbbfdfd400
Source dataset
uspto-grants-2013_04
Patent number
US08420650B2

Reaction notes

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