5-chloro-6-[4-(ethoxycarbonyl)piperidino]nicotinic acid

5-Chloro-6-[4-(ethoxycarbonyl)piperidino]nicotinic acid is mainly used as a raw material for the synthesis of the drug molecule avatrombopag.

5,6-Dichloronicotinic acid (7.68 g), anhydrous dioxane (200 mL), ethyl piperidine-4-carboxylate (12.6 g), and potassium hydrogen phosphate (17.4 g, 0.1 mol) were added to a 1000 mL round-bottom flask with a large neck. The reaction mixture was then stirred overnight under reflux (100°C). After the reaction was complete, the reaction mixture was cooled and filtered to remove most of the potassium salt. The resulting filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using a 2-10% methanol/CHCl3 solvent system to obtain the target product molecule 5-chloro-6-[4-(ethoxycarbonyl)piperidino]nicotinic acid.

[1] Kalgutkar*, A. S., Driscoll, J., Zhao, S. X., Walker, G. S., Shepard, R. M., Soglia, J. R., Atherton, J., Yu, L., Mutlib, A. E., Munchhof, M. J., Reiter, L. A., Jones, C. S., Doty, J. L., Trevena, K. A., Shaffer, C. L., & Ripp, S. L. (2007). A Rational Chemical Intervention Strategy To Circumvent Bioactivation Liabilities Associated with a Nonpeptidyl Thrombopoietin Receptor Agonist Containing a 2-Amino-4-arylthiazole Motif. Chemical Research in Toxicology, 20 12, 1954–1965. https://doi.org/10.1021/tx700270r