Chemical Properties
Crystal structure of 3-bromoisonicotinic acid (C6H4BrNO2): triclinic, P
ˉ1 (no. 2), a = 7.2512(6) ,
b = 7.3916(6) , c = 7.4920(7) , α = 65.065(4)°, β =
68.858(4)°, γ = 64.919(4)°, V = 321.60(5) 3
, Z = 2,
Rgt(F) = 0.0369, wRref(F
2
) = 0.1017, T = 150(2) K.
Uses
3-Bromoisonicotinic acid, as the most important intermediate in isonicotinic acid derivatives, is mainly used in the manufacture of anti-tuberculosis drugs, but also in the synthesis of amides, hydrazides, esters and other derivatives.
Synthesis
The general procedure for the synthesis of 3-bromoisonicotinic acid from 3-bromopyridine and carbon dioxide was as follows: 3-bromopyridine (164 mg, 1.0 mmol) was added to a solution of lithium diisopropylammonium (LiNPri2) in anhydrous tetrahydrofuran (THF, 1.0 M, 15 mL, 1.5 mmol) under the protection of argon (Ar), and the reaction mixture was stirred at -78 °C for 30 minutes. Subsequently, crushed solid carbon dioxide (CO2) was added under Ar protection and the cooling device was removed. The reaction mixture was allowed to warm up naturally to 20 °C with continuous stirring. After addition of water (10 mL), the organic solvent was removed by evaporation. The resulting aqueous phase was washed three times with ether (Et2O). Next, the pH was adjusted to 3 by adding 9 M hydrochloric acid (HCl) to the aqueous phase, and the mixture was stirred for 1 h. The mixture was then extracted three times with ethyl acetate (EtOAc). The organic phases were combined, washed with saturated saline (brine), dried and the solvent was evaporated to give the target product 3-bromoisonicotinic acid (20 mg, 10% yield) as white needle-like crystals. Its physical properties were as follows: melting point 175-176 °C (decomposition); 1H NMR (δ, ppm): 7.71 (1H, d, J = 4.8 Hz, 6-H), 8.70 (1H, d, J = 4.9 Hz, 5-H), 8.91 (1H, s, 2-H), 12.56 (1H, br, OH); 13C NMR (CDCl3, δ, ppm): 117.26 ppm): 117.26 (4-C), 123.77 (6-C), 148.94 (5-C), 152.61 (2-C), 165.00 (C=O), 166.07 (3-C); MS m/z: 202/200 (M-H)-.
References
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3013 - 3032
[2] Patent: EP2274983, 2011, A1. Location in patent: Page/Page column 126
[3] Patent: US2011/39843, 2011, A1. Location in patent: Page/Page column 79
[4] Patent: WO2011/40629, 2011, A1. Location in patent: Page/Page column 210
[5] Patent: WO2011/49220, 2011, A1. Location in patent: Page/Page column 209
