Synthesis
Concentrated sulfuric acid (2.00 mL) was added slowly and dropwise to a stirred solution of 3-chloro-4-aminobenzoic acid (2.00 g, 11.7 mmol) in methanol (20.0 mL) at 0 °C. The reaction mixture was warmed to 80 °C and kept stirring for 6 hours. Upon completion of the reaction, the mixture was cooled to room temperature and subsequently concentrated under reduced pressure. The concentrated residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-amino-3-chlorobenzoate (2.10 g, 97% yield). The product was confirmed by NMR hydrogen spectroscopy (400 MHz, DMSO-d6): δ 7.70 (d, J = 1.6Hz, 1H), 7.58 (dd, J = 8.4, 2.0Hz, 1H), 6.77 (d, J = 8.8Hz, 1H), 6.24 (s, 2H), 3.73 (s, 3H).
References
[1] Patent: WO2011/128251, 2011, A1. Location in patent: Page/Page column 203
[2] Patent: US2011/257151, 2011, A1. Location in patent: Page/Page column 75
[3] Patent: WO2018/157190, 2018, A1. Location in patent: Paragraph 0337
[4] Journal of Cellular Biochemistry, 2017, vol. 118, # 8, p. 2420 - 2429
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 666 - 680
