Sulfuric Acid → 5-bromo-7-chloroquinoline

Temperature

0 °C

To a suspension of 8-amino-5-bromo-7-chloroquinoline (700 mg, 2.72 mmol) in water (27 mL) at 0° C. was added concentrated sulfuric acid until the solid was mostly dissolved and the solution was a bright yellow. A solution of NaNO2 (375 mg, 5.44 mmol) in water (7 mL) was added dropwise to the stirring quinoline solution. After stirring at 0° C. for an additional 15 minutes, the cold solution was slowly added to stirring H3PO2 (6.5 mL, 54 mmol) at 65° C. Following complete addition of the cold solution, the mixture continued to be stirred at 65° C., and additional H3PO2 was added until the solution became colorless and no additional product formation was observed by LC/MS. Upon completion, the mixture was allowed to cool to room temperature, neutralized with 1M NaOH (aq), then extracted twice with EtOAc. The combined organics were washed with water (2×50 mL) then saturated NaCl (aq) (50 mL). The organics were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.95 (dd, J=1.4, 4.1 Hz, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.10 (d, =0.9 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.52 (dd, J=4.1, 8.5 Hz, 1H); LC6: 3.90 min. (M+H) 244.

1. dissolutionwas mostly dissolved
2. additionthe cold solution was slowly added
3. additionaddition of the cold solution
4. stirringto be stirred at 65° C.
5. temperatureto cool to room temperature
6. extractionextracted twice with EtOAc
7. washThe combined organics were washed with water (2×50 mL)
8. dry with materialThe organics were dried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customThe residue was purified by silica gel chromatography
12. washeluting with 0-5% EtOAc/hexanes

ORD record

ord-8bfb291a394441b4b31cde08e643b5a2

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08436015B2