Methane → 3-Amino-5-bromo-4-hydroxybenzonitrile

Temperature

65 °C

To a 22-l, 3-neck round-bottom flask fitted with a stirring paddle, a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen, and an addition funnel capped with a septum was added a mixture of 3-bromo-4-hydroxy-5-nitrobenzonitrile (96.9 g, Step A) in methanol (14 l). To this mixture was added iron (III) chloride (9.3 g) and activated charcoal (38 g, Darco 6-60, 100-mesh powder). The mixture was heated to reflux (65° C.) and stirred for 15 min at this temperature. Hydrazine (80 ml) was added to the refluxing mixture dropwise via addition funnel. Once the addition was complete, the mixture was stirred at reflux for 2 h. The mixture was then allowed to cool, filtered through Celite, washing with methanol, and concentrated to a red oil. A mixture of 300 ml of acetic acid and 700 ml of methanol was added and the mixture was concentrated again and then co-concentrated twice with 800 ml of toluene. The residue was purified by flash chromatography on an Isco Companion XL, 1.5 kg column, eluting with 3 column volumes of 30% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 30 to 60% over 6 column volumes, followed by 2 column volumes of 60% ethyl acetate in hexanes to provide 40 g (55%) of the title compound. Mass spectrum (ESI) 214.9 (M+1).

1. customa Claisen adapter fitted with a thermocouple and a condenser
2. customcapped with a septum
3. additionwas added
4. temperatureThe mixture was heated
5. additionOnce the addition
6. stirringthe mixture was stirred
7. temperatureat reflux for 2 h
8. temperatureto cool
9. filtrationfiltered through Celite
10. washwashing with methanol
11. concentrationconcentrated to a red oil
12. additionA mixture of 300 ml of acetic acid and 700 ml of methanol
13. additionwas added
14. concentrationthe mixture was concentrated again
15. customThe residue was purified by flash chromatography on an Isco Companion XL, 1.5 kg column
16. washeluting with 3 column volumes of 30% ethyl acetate in hexanes

ORD record

ord-43fe170c496c401ca1d68f1b352ef2e8

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08445480B2