A Two-Step Continuous Flow Synthesis of 4-Nitropyridine

Abstract

4-Nitropyridine, a key intermediate in medicinal products, was successfully prepared from pyridine N-oxide in a two-step -approach. Pyridine N-oxide was nitrated with HNO₃ and H₂SO₄ to give 4-nitropyridine N-oxide, followed by reaction with PCl₃ to give the final product. The continuous flow methodology was used to minimise accumulation of the highly energetic and potentially explosive nitration product to enable the safe scale-up of 4-nitropyridine with no 2-nitropyridine by-product. By employing continuous extraction in the nitration step and applying the optimised conditions, a throughput of 0.716 kg 4-nitropyridine product per day from pyridine N-oxide with 83% yield and high selectivity in a continuous flow system was achieved.