3-Bromo-1-propanol → [2-(3-Bromo-propoxy)-5-fluoro-4-nitro-phenyl]-ethylamine

Temperature

0 °C

2-Ethylamino-4-fluoro-5-nitro-phenol (910 mg, 4.5 mmol) was azeotroped with toluene to ensure dryness, then was dissolved in Tetrahydrofuran (100 mL) and was cooled at 0° C. 3-Bromo-1-propanol (0.65 mL, 7.2 mmol), Tributylphosphine (2.0 mL, 8.2 mmol), and 40% w/w DEAD in Toluene (3.8 g, 8.7 mmol) were added in succession, and the reaction was stirred under an atmosphere of Nitrogen overnight. The mixture was conc. in vacuo onto silica gel (10 g) and chromatographed (ISCO, 80 g silica gel, 0-35% EtOAc:Hex) to afford [2-(3-Bromo-propoxy)-5-fluoro-4-nitro-phenyl]-ethylamine as an orange solid. The bromide was dissolved in Tetrahydrofuran (100 mL) and Sodium hydride, 60% disp. in mineral oil (0.20 g) was added. After 2 h, no reaction was observed, so N,N-Dimethylformamide (5 mL) was added. After o.n. stirring, no reaction, so additional Sodium hydride, 60% disp. in mineral oil (0.35 g) was added and the mixture was heated at 65° C. After 4 h, the reaction was complete and was cooled to rt. The reaction was quenched with water, diluted with ether (300 mL) and washed with water (40 mL), satd. sodium bicarbonate (2×40 mL) and brine (80 mL), dried over sodium sulfate and conc. in vacuo onto 6 g silica gel. Chromatography (ISCO, 80 g silica gel, 0-30% EtOAc:Hex) afforded 9-Ethyl-2-fluoro-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (517 mg, 47% two steps). 1H-NMR (CDCl3): 7.62 (d, 1H, J=7.9 Hz), 6.33 (d, 1H, J=14 Hz), 4.21 (t, 2H, J=6.5 Hz), 3.63 (t, 2H, J=5.8 Hz), 3.35 (q, 2H, J=7.0 Hz), 2.12 (m, 2H), 1.25 (t, 3H, J=7.0 Hz).

1. customchromatographed (ISCO, 80 g silica gel, 0-35% EtOAc:Hex)

ORD record

ord-400af7fa9b504067bb9214608a02b9e0

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08148391B2