Synthesis
Step B. Synthesis of 5-bromo-2-chloronicotinic acid. A mixture of 5-bromo-2-hydroxynicotinic acid (32.9 g, 0.151 mol), dichlorosulfoxide (167 mL), and N,N-dimethylformamide (10.5 mL) was heated to reflux for 4 hours at 70°C. The reaction was carried out with the addition of water. Upon completion of the reaction, the mixture was concentrated, cooled to 0°C, and the reaction was quenched by the slow addition of water to give an off-white precipitate. The precipitate was stirred in water for 1 h and subsequently collected by filtration and dried under vacuum to give 5-bromo-2-chloronicotinic acid (35.5 g, 99% yield). The product can be used directly in the subsequent reaction without further purification or can be purified by recrystallization in hot water. Mass spectrum (electrospray ionization): calculated value C6H3BrClNO2, 234.90; measured value m/z, 236.2 [M + H]+. 1H NMR (acetone-d6): δ 8.66 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H).
References
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2566 - 2569
[2] Patent: US2006/287292, 2006, A1. Location in patent: Page/Page column 26
[3] European Journal of Organic Chemistry, 2010, # 28, p. 5397 - 5401
[4] Synthetic Communications, 1989, vol. 19, # 3and4, p. 553 - 560
[5] Patent: WO2010/136817, 2010, A1. Location in patent: Page/Page column 113
