3-[(4-bromophenyl)amino]propanoic acid

Synthesis

a) 4-Bromoaniline (2.0 g, 11.6 mmol) and acrylic acid (0.95 mL, 13.9 mmol) were reacted in toluene (15 mL) with stirring at 100 °C for 3 days. After completion of the reaction, it was cooled to room temperature and extracted with 1N NaOH solution (150 mL). The aqueous phase was adjusted to pH ~3 with 2N HCl and subsequently extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-(4-bromophenyl)-3-aminopropionic acid (1.65 g, 58%). b) The above carboxylic acid product (1.64 g, 6.72 mmol) was dissolved in polyphosphoric acid (30 g) and the reaction was stirred at 90 °C overnight. After completion of the reaction, it was cooled to room temperature and the reaction was quenched by the addition of ice water. The mixture was extracted with ethyl acetate (2 x 200 mL). The organic phases were combined and washed sequentially with 1N NaOH, water and saturated saline. After drying with anhydrous sodium sulfate, it was concentrated under reduced pressure to give the cyclized product (0.88 g, 58%). 1H NMR (CDCl3) δ (ppm): 2.67 (t, 2H), 3.54 (t, 2H), 6.57 (d, 1H), 7.33 (dd, 1H), 7.92 (s, 1H).

References

[1] Patent: WO2009/39553, 2009, A1. Location in patent: Page/Page column 93
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 9, p. 2801 - 2807