Scale-up and optimisation of the β-chloroacrylamide process by batch and continuous flow methods

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Dennehy, Olga C.
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University College Cork
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α-Thio-β-chloroacrylamides are a class of highly versatile synthetic intermediates due to their diverse functionality. The three step synthesis to form these compounds provided a model system to optimise and scale-up a complex API-like process through advanced process control to yield the final product with optimum quality and phase purity. The first chapter of this thesis presents an overview of the mechanistic pathway leading to the formation of these compounds along with the different process tools available for optimisation. It covers the various factors for consideration in industrial process development and it delves into the field of continuous flow chemistry, assessing the advantages and limitations associated with the technology, and its application in an industrial setting. It also includes a summary of crystallisation and solid state screening as an important stage in industrial process development, especially in API synthesis. The second chapter consists of the optimisation and scale-up of the first and second steps of the process to produce the starting material for the cascade reaction (third step). It addresses the issues associated with scaling-up a highly exothermic reaction in the first step and poor reaction efficiency and impurity management in the second step. This work effectively utilises both continuous flow and batch processing to exploit the inherent advantages of both methodologies for the specific requirements of each reaction, and affords readily scalable processes. The third chapter explores the final step of the synthesis, which consists of a complex chlorination cascade to form the α-thio-β-chloroacrylamide. Producing the desired product required a high level of control over heat transfer and reaction stoichiometry, which was possible at scale by applying continuous flow methodologies (as this multistep reaction would not have been scalable in batch). Optimising this step took a broader approach to process development, addressing issues commonly posed in the final step of API production. This was achieved by incorporating the application of a more compatible reaction solvent for continuous processing, scaling-up the reaction, managing process impurities, developing an inline work-up to remove reaction by-products, designing a continuous liquid-liquid separator (to implement the inline work-up), establishing product solubility for isolation by crystallisation and monitoring the solid state properties of the final product.
Scale-up , Optimisation , Crystallisation , β-chloroacrylamide , Continuous flow , Process impurities , Continuous processing , Process chemistry
Dennehy, O. C. 2020. Scale-up and optimisation of the β-chloroacrylamide process by batch and continuous flow methods. PhD Thesis, University College Cork.
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