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

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dc.contributor.advisor Moynihan, Humphrey A. en
dc.contributor.advisor Maguire, Anita en
dc.contributor.author Dennehy, Olga C.
dc.date.accessioned 2021-01-06T10:58:33Z
dc.date.available 2021-01-06T10:58:33Z
dc.date.issued 2020-04
dc.date.submitted 2020-04
dc.identifier.citation Dennehy, O. C. 2020. Scale-up and optimisation of the β-chloroacrylamide process by batch and continuous flow methods. PhD Thesis, University College Cork. en
dc.identifier.endpage 266 en
dc.identifier.uri http://hdl.handle.net/10468/10858
dc.description.abstract 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. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2020, Olga C. Dennehy. en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Scale-up en
dc.subject Optimisation en
dc.subject Crystallisation en
dc.subject β-chloroacrylamide en
dc.subject Continuous flow en
dc.subject Process impurities en
dc.subject Continuous processing en
dc.subject Process chemistry en
dc.title Scale-up and optimisation of the β-chloroacrylamide process by batch and continuous flow methods en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD - Doctor of Philosophy en
dc.internal.availability Full text not available en
dc.description.version Accepted Version en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en
dc.internal.school Chemistry en
dc.check.chapterOfThesis Pages 160-168: 3.3.2 E-isomer Pages 179-184: 3.4.1 Development of a Continuous Separator Pages 187-204: 3.5 Solid State Analysis of the α-Thio-β-chloroacrylamide Final Product Z-1 Page 206: Scheme 3.15 Pages 222-223 Separator data in Experimental (Page numbers printed on the document pages) en
dc.internal.conferring Spring 2021 en
dc.internal.ricu Synthesis and Solid State Pharmaceutical Centre (SSPC) en
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2275/IE/Synthesis and Solid State Pharmaceutical Centre (SSPC)/ en
dc.availability.bitstream controlled
dc.check.date 2030-06-01


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© 2020, Olga C. Dennehy. Except where otherwise noted, this item's license is described as © 2020, Olga C. Dennehy.
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