Synthesis
Step 2: The crude product 4-(4-bromophenoxy)butyric acid ethyl ester obtained in step 1 was dissolved in methanol (100 mL) and 3N aqueous sodium hydroxide solution (200 mL) was added. The reaction mixture was heated to 70 °C and kept for 1 hour for hydrolysis reaction. Upon completion of the reaction, the mixture was poured into ice water and 37% aqueous hydrochloric acid (50 mL) was slowly added to neutralize the reaction system. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the crude product. The crude product was ground with ether to give 4-(4-bromophenoxy)butyric acid (41 g, 79% yield, two steps) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm: 2.12-2.16 (m, 2H), 2.61 (t, J = 7.0 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 6.78 (d,. J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H).
References
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 10, p. 2049 - 2063
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 914 - 923
[3] Patent: WO2016/25932, 2016, A1. Location in patent: Page/Page column 150; 151
[4] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 9971 - 9974
