Hydrochloric Acid → 2-Bromo-5-chloro-4-methyl-benzoic acid methyl ester

HRID 1175292Notes

Reaction equation

HRID 1175292 reaction equation
N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[ClH:14].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]

Participants

7

Reactant 3

HCID 313Hydrochloric Acid2×HCID 23668193Sodium NitriteHCID 56924477Methyl 5-amino-2-bromo-4-methylbenzoate

Product 1

HCID 533306162-Bromo-5-chloro-4-methyl-benzoic acid methyl ester

Reagents, catalysts & solvents 3

HCID 62652Cuprous chlorideCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
5 °C

Procedure

To a cooled solution (15° C.) of methyl 5-amino-2-bromo-4-methylbenzoate (122 g, 0.5 mol) in 1,4-dioxane (633 mL), was added conc. hydrochloric acid (550 mL). After the mixture was cooled to 5° C., a solution of sodium nitrite (35.53 g, 0.515 mol) in 83 mL of H2O was added dropwise at such a rate that the reaction temperature was kept below 0° C. After being stirred at 0° C. for 2 h, the reaction mixture was added slowly to a flask containing copper (I) chloride (59.4 g, 0.6 mol) and conc. hydrochloric acid (275 mL). It was stirred for 40 min, at which time TLC demonstrated that the reaction was complete. The reaction mixture was poured over ice water (2 L) and then filtered. The filter cake was dissolved in EtOAc (1.5 L). The organic layer was washed with brine (3×500 mL) and then dried over anhydrous Na2SO4 Concentration under reduced pressure provided the title compound as light yellow crystals. Yield: 120 g (92.6%). 1H-NMR (CDCl3, 300 MHz): δ 7.82 (s, 1H), 7.54 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H); MS ESI (m/z) 262 (M)+, calc. 262.

Workup

  1. customwas kept below 0° C
  2. additionthe reaction mixture was added slowly to a flask
  3. stirringIt was stirred for 40 min, at which time TLC
  4. filtrationfiltered
  5. dissolutionThe filter cake was dissolved in EtOAc (1.5 L)
  6. washThe organic layer was washed with brine (3×500 mL)
  7. dry with materialdried over anhydrous Na2SO4 Concentration under reduced pressure

Sources & evidence

ORD record
ord-85f70de560e24472b4fa20ed3265601d
Source dataset
uspto-grants-2010_11
Patent number
US07838498B2

Reaction notes

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