Hydrogen Bromide → 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one

To a solution of tert-butyl [8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77c, 500 mg, 0.282 mmol) in THF (20 mL) was added HBr (10.0 mL, 88.4 mmol, 48% aqueous solution). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C., CuBr (303 mg, 2.11 mmol) was added, followed by addition of NaNO2 (1.07 mL, 1.55 mmol, 100 mg/mL solution). The resulting reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was neutralized with NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (1×100 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100% EtOAc/heptanes) to give 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 42% over two steps) as a solid.

1. temperatureThe reaction mixture was cooled to 0° C.
2. customThe resulting reaction mixture
3. stirringwas stirred at 0° C. for 1.5 hours
4. extractionextracted with ethyl acetate (2×50 mL)
5. washThe combined organic phases were washed with brine (1×100 mL)
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated under vacuum
8. custompurified by column chromatography (0-100% EtOAc/heptanes)

ORD record

ord-3e85b0e2b7be4d4697b48db9e5e193a8

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040515B2