Methyl 5-bromo-2-chloropyridine-3-carboxylate

The crystal structure data of Methyl 5-bromo-2-chloropyridine-3-carboxylate is shown below:

Methyl 5-bromo-2-chloropyridine-3-carboxylate is a useful intermediate for the synthesis of various bioactive compounds[6]. Methyl 5-bromo-2-chloropyridine-3-carboxylate serves as a starting material to prepare methyl 5-bromo-2-fluoropyridine-3-carboxylate by treatment with cesium fluoride[7].

Methyl 5-bromo-2-chloropyridine-3-carboxylate is prepared by the reaction of 5-Bromo-2-chloronicotinic acid and Methanol. The specific synthesis steps are as follows:
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4(5 mL). The mixture was heated to 60° C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2(200 mL). The organic layer was separated, washed with brine, dried over MgSO4and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1.

[1] Patent: US2012/172391,  2012,  A1. Location in patent: Page/Page column 79
[2] Journal of Agricultural and Food Chemistry,  2016,  vol. 64,  # 18,  p. 3533 - 3537
[3] Patent: WO2014/186398,  2014,  A1. Location in patent: Page/Page column 49; 50; 51
[4] Patent: WO2017/120429,  2017,  A1. Location in patent: Page/Page column 263
[5] Patent: US2012/178776,  2012,  A1. Location in patent: Page/Page column 42-43
[6]Ma, Y., & Liu, Y.-L. (2008). Methyl 5-bromo-2-chloropyridine-3-carboxylate. Acta Crystallographica Section E Structure Reports Online, 64(6), o1072–o1072. https://doi.org/10.1107/s1600536808013305
[7]Kaieda, A., Takahashi, M., Fukuda, H., Okamoto, R., Morimoto, S., Gotoh, M., Miyazaki, T., Hori, Y., Unno, S., Kawamoto, T., Tanaka, T., Itono, S., Takagi, T., Sugimoto, H., Okada, K., Snell, G., Bertsch, R., Nguyen, J., Sang, B., & Miwatashi, S. (2019). Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1. ChemMedChem, 14(10), 1022–1030. https://doi.org/10.1002/cmdc.201900129