N-bromobutanimide → HCID 68107558, compound

To a stirring solution of 3-fluoro-2-tetrahydrofuran-2-yl-aniline (16) (131.9 g, 92%, 669.7 mmol) in methyl tert-butyl ether (1.456 L) and acetonitrile (485 mL) cooled to −20° C. was added N-bromosuccinimide (120.4 g, 99%, 669.7 mmol, Aldrich B81255) in 3 portions maintaining a reaction temperature below about −15° C. After complete addition, stirring was continued at −15 to −10° C. for 30 minutes. 1H NMR of a worked-up aliquot showed 96% consumption of starting aniline. Another 4.82 g NBS was added to the reaction mixture and stirred at −10° C. for additional 30 minutes. Aqueous 1 N Na2S2O3 (670 mL) was added to the reaction mixture. The cold bath was removed, the mixture stirred for 20 minutes, then diluted with EtOAc. The layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (2×), water, and brine, dried over Na2SO4, decanted, and concentrated under reduced pressure giving a dark amber oil. The residue was diluted with hexane and eluted through a short plug of silica with 25% EtOAc/hexane to 50% EtOAc/hexane. The desired filtrate was concentrated in vacuo giving 17 as dark amber oil (182.9 g, 90% yield; 86% NMR purity). LCMS (C18 column eluting with 10-90% AcN/water gradient over 5 minutes with formic acid modifier) M+1: 260.12 (3.20 min). 1H NMR (300 MHz, CDCl3) δ 7.15 (dd, J=8.6, 7.6 Hz, 1H), 6.30 (dd, J=8.7, 1.3 Hz, 1H), 5.19-5.12 (m, 1H), 4.58 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-1.99 (m, 4H) ppm.

1. temperaturemaintaining a reaction temperature below about −15° C
2. additionAfter complete addition
3. custom96% consumption of starting aniline
4. additionAnother 4.82 g NBS was added to the reaction mixture
5. stirringstirred at −10° C. for additional 30 minutes
6. additionAqueous 1 N Na2S2O3 (670 mL) was added to the reaction mixture
7. customThe cold bath was removed
8. stirringthe mixture stirred for 20 minutes
9. additiondiluted with EtOAc
10. customThe layers were separated
11. washThe organic phase was washed with saturated aqueous NaHCO3 (2×), water, and brine
12. dry with materialdried over Na2SO4
13. customdecanted
14. concentrationconcentrated under reduced pressure
15. customgiving a dark amber oil
16. washeluted through a short plug of silica with 25% EtOAc/hexane to 50% EtOAc/hexane
17. concentrationThe desired filtrate was concentrated in vacuo

ORD record

ord-85740b66d4c046cfa0825617f617e874

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08912326B2