Some Issues and Their Solutions in the Process Development of Ethyl 2-(4-Aminophenoxy)thiazole-5-carboxylate: A Key Intermediate of P2X3 Antagonist

Ethyl 2-(4-aminophenoxy)thiazole-5-carboxylate is a key intermediate of several P2X3 antagonists required for clinical trials. The synthesis at the early R&D stage delivered this thiazole derivative via a nucleophilic aromatic substitution reaction in highly variable yields, from 7 to 85%. We describe the process development of the initial route of synthesis carefully considering the reaction conditions, process robustness and safety, operational improvement, and the impact on downstream steps. The optimized process was successfully replicated on a multikg scale in a pilot plant, allowing for the supply of the key intermediate in 90% isolated yield with high purity (>99 area%).