Continuous Scalable Synthesis and Concentration Variation of Organozinc Compounds

Abstract

In the production of pharmaceutically active ingredients, the formation of new carbon–carbon bonds is essential. A widespread and frequently employed method is the use of organometallic reagents (e.g., RLi, RMgX, RZnX), which differ greatly in their reactivity and are selected according to the specific reaction pathway desired. Organozinc compounds (RZnX) represent a class of compounds whose reactivity is lower than that of the widely used Grignard reagents and far below that of organolithium compounds, allowing them to tolerate the presence of functional groups incompatible with organomagnesium and organolithium compounds. Organozinc compounds are highly sensitive to oxygen and moisture, which results in difficult handling and problematic storage and limits the use of organozinc compounds in synthetic chemistry. In order to overcome this limitation and make organozinc reagents widely accessible for process chemists of varying industries, a continuous synthetic route to a large number of organozinc reagents was established on a laboratory and pilot scale. Flow rates, solvents, the metal activation mechanism, and the initial concentration of the starting materials were varied. For this purpose, a bed of Zn granules was used, which provides an approximately 250-fold excess of Zn throughout the reaction. The formed zinc organyls were analyzed by manual titration and GC analysis after quenching to determine conversion and yield as well as possible side product formation. For the formation of monozinc organyls, a lab-scale reactor originally designed for the formation of Grignard reagents was used, including a Zn replenishing unit. The main objective of this work was to establish the scalable continuous formation of organozinc reagents, which enables fast and safe process optimization. It was found that complete conversion of the organic halides used could be achieved in a single passage through the reactor with zinc organyl yields of 78–100%. Furthermore, the continuous conversion of highly concentrated 2.0 M starting materials was successfully carried out for the first time. Sufficient process reliability was ensured, and good to very good yields of 84–100% were demonstrated. The synthesis of some selected zinc organyls was then also transferred to a pilot scale, where a maximum liquid throughput of 18 L/h was achieved. With residence times of 1.5–14.0 min, complete conversion of the organic halide was achieved in all syntheses with high zinc organyl yields of up to 98%.