General procedure for the synthesis of 2,6-dibromo-3-aminopyridine from 3-aminopyridine:
Method F; Example F-1; 4-({6-bromo-2-oxo-1-[2-(trifluoromethyl)benzyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3-ylmethyl})benzoic acid; F-1-a Preparation of 2,6-dibromo-3-pyridinamine.
Reference to Majumdar, K.C.; Mondal, S. (Regioselective synthesis of substituted pyrrolidinopyridines based on Pd(II)-mediated cross-coupling and base-induced heterocyclization. Springer. 2007, 48, 6951-6953), 3-aminopyridine (4.75 g, 50.5 mmol) was dissolved in a mixture of DMSO (100 mL) and water (2.5 mL) at 0 °C, and N-bromosuccinimide (18.9 g, 8.91 mmol) was added in batches. The reaction mixture was stirred at room temperature for 24 hours. The solid formed during the reaction was collected by filtration and dried over a glass stock. Subsequently, the dried solid was dissolved in ethyl acetate, dried with sodium sulfate and filtered. The solvent was removed by vacuum evaporation to give a reddish brown solid product (11.7 g, 92%). The product was used directly in the subsequent reaction without further purification and its 1H NMR spectrum was in agreement with literature reports (Parlow, J.J.; Kurumbail, R.G.; Stegeman, R.A.; Stevens, A.M.; Stallings, W.C.; South, M.S. Design, Synthesis and Crystal Structure of Selective 2-Pyridone Tissue Factor VIIa Inhibitors. (J. Med. Chem. 2003, 46, 4696-4701) conform.
