Synthesis
General procedure for the synthesis of ethyl 4,6-dichloroquinoline-3-carboxylate from ethyl 4-hydroxy-6-chloroquinoline-3-carboxylate: a 5-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester (DK-I-34-1, 85.1 g, 338.1 mmol), N,N-dimethylformamide (1.0 mL, 12.9 mmol) and dichloromethane (640 mL) The mixture was heated to 35-40°C. Oxalyl chloride (47.2 g, 371.9 mmol) was added slowly and dropwise to the reaction mixture over 30 minutes. The reaction mixture was then heated at reflux temperature (38-40 °C) for 6 hours. Upon completion of the reaction, the resulting light yellow solution was cooled to 20-25 °C. The reaction mixture was neutralized by slow addition of 25% aqueous potassium carbonate solution (75 g of potassium carbonate dissolved in 300 mL of water). The organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 25% aqueous potassium carbonate (50 g potassium carbonate dissolved in 200 mL of water) and subsequently dried over magnesium sulfate. The solvent was removed by rotary evaporator and the product residue was slurried with hexane (200 mL). The solid product was filtered and washed twice with hexane (50 mL x 2). The solid was dried to give the off-white solid product DK-I-35-1 (81.9 g, 90% yield). The structure of the product was determined by 1H NMR (300 MHz, DMSO) δ 9.13 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.97 (dd, J=9.0,2.3 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz , 3H); 13C NMR (75 MHz, DMSO) δ 164.01,150.53,147.73,141.04,134.30,133.34,132.20,126.53,124.37,124.08,62.59; HRMS m/z calculated value C12H10Cl2NO2 (M+H)+ 270.0088, measured value 270.10 confirmed.
References
[1] Patent: WO2016/196961, 2016, A1. Location in patent: Paragraph 00148
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2422 - 2446
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3578 - 3582
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 11, p. 1669 - 1673
[5] Farmaco, 1998, vol. 53, # 8-9, p. 579 - 585
