Synthesis
Ethyl 7-bromo-4-hydroxyquinoline-3-carboxylate (DK-I-49-1, 11.0 g, 37.1 mmol) was heated to 35-40 °C in a solvent mixture of N,N-dimethylformamide (0.1 mL, 1.3 mmol) and dichloromethane (50 mL). Oxalyl chloride (5.2 g, 40.9 mmol) was slowly added dropwise to the reaction mixture over 30 minutes. Subsequently, the reaction mixture was heated at reflux temperature (38-40 °C) for 1 hour. After completion of the reaction, the resulting brown solution was cooled to 20-25 °C. The reaction mixture was diluted with dichloromethane (150 mL) and then neutralized by slowly adding 25% aqueous potassium carbonate solution (12.5 g potassium carbonate dissolved in 50 mL of water). The organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined and washed with 25% aqueous potassium carbonate (12.5 g potassium carbonate dissolved in 50 mL of water). The combined organic layers were dried over magnesium sulfate. The solvent was removed by rotary evaporation and the product residue was slurried with hexane (50 mL). The solid product was filtered and washed twice with hexane (25 mL x 2). The solid was dried to afford the target product ethyl 4-chloro-7-bromoquinoline-3-carboxylate (DK-I-54-1, 7.2 g, 61% yield) as an off-white solid. The structure of the product was confirmed by 1H NMR, 13C NMR and HRMS: 1H NMR (300 MHz, DMSO) δ 9.15 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.98 (dd, J = 9.0, 1.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 164.04, 151.40, 149.74, 142.34, 132.67, 131.88, 127.50, 126.64, 124.70, 123.96, 62.55, 14.46. HRMS m/z calculated for C12H10BrClNO2 (M + H)+ 313.9583, found 314.05.
References
[1] Patent: WO2016/196961, 2016, A1. Location in patent: Paragraph 00150
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2422 - 2446
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 8, p. 1487 - 1490
