Sodium Sulfite → Methyl 4-Bromo-3-hydroxybenzoate

Temperature

100 °C

To a suspension of methyl 4-amino-3-hydroxybenzoate 69 (21.7 g, 127 mmol) in water (115 mL) at 0° C. was added a solution of sodium nitrite (9.1 g, 127 mmol) in water (50 mL). The resultant mixture was stirred at 0° C. for 1 h. Meanwhile, copper sulfate pentahydrate (42.4 g, 169 mmol) was dissolved in water (135 mL) with heating and sodium bromide (26.4 g, 257 mmol) was added slowly with stirring. The resultant dark green solution was stirred for 5 min, and then was treated with a solution of sodium sulfite (11.3 g, 90 mmol) in water (40 mL). The resultant lime green slurry was stirred for 5 min, and then cooled by the addition of ice. The ice water was decanted off, carefully avoiding dryness. The residue was rinsed with water (3×) and the resultant white solid was dissolved in 115 mL concentrated HBr (115 mL). This acidic copper bromide solution was added to the diazonium salt suspension (see above) at 0° C. The resultant mixture was gradually heated up to 100° C., then stirred at this temperature for 1 h. Significant foaming was observed. After this time, the reaction mixture was cooled and brought to pH 4–5 by the addition of sodium carbonate. EtOAc was added and the mixture was filtered. The filtrate was extracted with EtOAc (3×). The organic layers were dried over Na2SO4 and filtered to give 70. 1H NMR (400 MHz CDCl3) δ: 3.91 (s, 3H), 5.81 (br s, 1H), 7.48 (dd, J=8.5 Hz, 1.4 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.68 (s, 1H). MS (EI) m/z (M−H−) 229.

1. temperaturewith heating
2. stirringThe resultant dark green solution was stirred for 5 min
3. temperaturecooled by the addition of ice
4. customThe ice water was decanted off
5. washThe residue was rinsed with water (3×)
6. dissolutionthe resultant white solid was dissolved in 115 mL concentrated HBr (115 mL)
7. additionThis acidic copper bromide solution was added to the diazonium salt suspension (see above) at 0° C
8. stirringstirred at this temperature for 1 h
9. temperatureAfter this time, the reaction mixture was cooled
10. additionbrought to pH 4–5 by the addition of sodium carbonate
11. additionEtOAc was added
12. filtrationthe mixture was filtered
13. extractionThe filtrate was extracted with EtOAc (3×)
14. dry with materialThe organic layers were dried over Na2SO4
15. filtrationfiltered

ORD record

ord-eb86b00de2684f24ba5fcacaf1176f64

Source dataset

uspto-grants-2007_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07199119B2