(343a) Continuous Flow Synthesis of Grignard Reagents Towards the Preparation of Advanced Intermediates and Active Pharmaceutical Ingredients – a Modular Approach

Grignard reagents remain a cornerstone for carbon-carbon bond formation in organic synthesis and in the pharmaceutical industry; however, their traditional batch preparation suffers greatly from safety concerns due to the pyrophoric nature of magnesium, the exothermic nature of the reaction, and the corrosive nature of the final solution. In recent years, the use of continuous flow chemistry and continuous flow manufacturing strategies have been used to palliate for these limitations. This work explores the application of continuous flow chemistry coupled with process analytical tools (PAT), chemometric and mechanistic modelling for the safe, efficient, and scalable generation of Grignard Reagents and their subsequent use in telescoped processes. Herein, we demonstrate the in-situ activation of magnesium metal and its subsequent reaction with two organic halides R-Br (1) and R-Cl (6) under continuous flow conditions using PAT (in-line IR and NMR) for reaction monitoring and process control.

Case Study 1 (Figure 1a): Upon optimization of the reaction parameters under conventional batch conditions and transpositions under continuous flow, we managed to increase the conversion into our desired Grignard species (2) from ca. 85% up to 96%. Then, using tailored chemometric and mechanistic models to monitor the various species involved, the process was run in a closed-loop system under model predictive control for ca. 48h to mimic a manufacturing run. This extended run yielded a daily productivity of up to 1.5 kg of the final material after downstream purification and highlighted the efficiency and robustness of the developed modular platform and process.

Case Study 2 (Figure 1b): The modular platform developed in Case Study 1 was repurposed for the preparation of a second Grignard reagent. Upon optimization of the reaction parameters and transposition under continuous flow, the conversion into the corresponding Grignard species (7) increased from ca. 85% up to 98%. Following the same strategy of combining chemometric and mechanistic models to monitor the various species, the platform was run for 10h yielding a productivity of up to 710 g a day in the corresponding Grignard species. A 7-day run of the platform is planned to mimic the duration of a manufacturing run. Successful execution will demonstrate the robustness and manufacturing-readiness of the devised modular platform.

This work demonstrates the significant improvement achievable for Grignard reagent generation through the combination of continuous flow chemistry, PAT, and modelling compared to traditional batch methods. In two case studies, the conversion of organic halides to the desired Grignard reagents increased substantially (up to 98% from 85%). Furthermore, continuous flow operations with PAT and model-based control enabled multi-day operation, achieving daily productivities of 1.5 kg and 710 g for the respective Grignard products. These results highlight the efficiency and robustness of the developed platform, paving the way for the safe and scalable manufacturing of Grignard reagents within the pharmaceutical industry and beyond. Future work will focus on further extending the platform’s capabilities and demonstrating its robustness through extended manufacturing-mimicking runs for the second case study. This will solidify the approach as a viable and advantageous alternative to traditional batch methods for Grignard reagent generation.