Hydrogen Bromide → 6-(N-(4-Bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Temperature

60 °C

To a 1 L 3-necked flask equipped with a mechanical stirrer was added 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 18.9 mmol) followed by acetonitrile (200 mL) and then 48% aqueous HBr (200 mL). A thick, lumpy suspension resulted which was stirred vigorously for 30 minutes to afford a more uniform suspension. The reaction vessel was cooled in an ice water bath for 30 minutes and the mixture treated with a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (20 mL) via addition funnel over 5 minutes. The resulting yellow suspension was stirred in the ice bath for 1.5 hours and then treated with CuBr (4.1 g, 28.4 mmol) in small portions over 5 minutes. This afforded a dark brown solution that was warmed to 60° C. (internal temperature) with continued stirring. After 40 minutes at elevated temperature the mixture was cooled to RT and poured into a rapidly stirred mixture of 5% aqueous sodium bisulfite (600 mL) and EtOAc (800 mL). The phases were separated and the aqueous solution extracted with two additional 150 mL portions of EtOAc. The combined EtOAc solutions were washed with 5% aqueous sodium bisulfite (2×150 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×200 mL), dried over sodium sulfate and concentrated to dryness at reduced pressure to give a yellow foam. This material was subjected to flash chromatography (silica gel, gradient from 9:1 hexane/EtOAc to EtOAc). During concentration of the pure fractions a white solid crystallized out. After concentrating down to a thick suspension the mixture was diluted with 150 mL of hexane and the mixture stirred at RT overnight. The solid was collected by filtration in a medium fritted funnel and dried in vacuo to afford the title compound (8.55 g, 76%) as a white crystalline solid. LCMS (m/z, ES+)=591,593 (M+H+).

1. customTo a 1 L 3-necked flask equipped with a mechanical stirrer
2. customA thick, lumpy suspension resulted which
3. customto afford a more uniform suspension
4. temperatureThe reaction vessel was cooled in an ice water bath for 30 minutes
5. customThis afforded a dark brown solution that
6. temperatureAfter 40 minutes at elevated temperature the mixture was cooled to RT
7. customThe phases were separated
8. extractionthe aqueous solution extracted with two additional 150 mL portions of EtOAc
9. washThe combined EtOAc solutions were washed with 5% aqueous sodium bisulfite (2×150 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×200 mL)
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated to dryness at reduced pressure
12. customto give a yellow foam
13. customDuring concentration of the pure fractions a white solid crystallized out
14. concentrationAfter concentrating down to a thick suspension the mixture
15. additionwas diluted with 150 mL of hexane
16. stirringthe mixture stirred at RT overnight
17. filtrationThe solid was collected by filtration in a medium fritted funnel
18. customdried in vacuo

ORD record

ord-2186bf59b6094e639c968948064867a1

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09119868B2