Development and pilot scale implementation of safe aerobic Cu/TEMPO oxidation in a batch reactor

Abstract

In the pharmaceutical industry, the development of a safe, cost effective, productive, and sustainable process remains an exciting challenge that has to be solved to minimize the negative environmental impact caused by the huge quantity of reagents/solvents used. In this context, alcohol oxidation is probably one of the most challenging reactions, due to the inherent toxicity and the disposal issues associated with most of the available oxidants on the market. Herein, we describe our efforts to replace the use of toxic and expensive stoichiometric DDQ in the oxidation of a benzylic primary alcohol 2 in the phase II Servier clinical candidate S44819 manufacturing route. Screening of commonly used oxidants led to the identification and development of a highly efficient, selective and ecocompatible aerobic copper/TEMPO catalytic system, demonstrated by the improvement of green chemistry/sustainability metrics and reagents' cost from the original to the newly developed process. Gas–liquid mass transfer, safety assessment related to the use of air in a batch reactor and calorimetric analysis are discussed and this highly atom economical and low-cost aerobic oxidation was safely implemented at the pilot scale, enabling the manufacture of 13.3 kg of high-quality key intermediate 1.