Synthesis
Example 5: Preparation of 3-chloro-4-(3-fluorobenzyloxy)aniline
In a 1 L reactor, 35.6 g of Intermediate-A (3-chloro-4-(3-fluorobenzyloxy)nitrobenzene), 21.2 g of iron powder (70 mesh), and 60.9 g of ammonium chloride were dissolved in a solvent mixture of 506 mL of ethanol and 128 mL of water, and the reaction was carried out at reflux for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to 20-25 °C and the insoluble iron oxide was removed by vacuum filtration. The solid obtained by filtration was washed with ethanol. The filtrates were combined and the solvent was removed by evaporation to give 94.9 g of a highly moist orange solid. The solid was mixed with 400 mL of dichloromethane to dissolve the organic product. The turbid solution was filtered to remove inorganic salts. The filtrate was transferred to a partition funnel to separate the organic phase and remove the aqueous residue. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give 30.8 g of 3-chloro-4-(3-fluorobenzyloxy)aniline (Yield: 96%, Purity as determined by HPLC: 99.67%, Major impurity content: 0.10%).
References
[1] Patent: US2004/53946, 2004, A1
[2] Patent: US2015/366868, 2015, A1. Location in patent: Paragraph 0158
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[4] Patent: WO2009/33581, 2009, A1. Location in patent: Page/Page column 59-60
[5] Patent: WO2009/63054, 2009, A1. Location in patent: Page/Page column 68-69
