DOI
https://doi.org/10.25772/RWHS-HD76
Author ORCID Identifier
https://orcid.org/0000-0001-5135-3015
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
B. Frank Gupton
Second Advisor
James Ferri
Third Advisor
Heather Lucas
Fourth Advisor
Matthew Hartman
Fifth Advisor
Suzanne Ruder
Abstract
Continuous flow as a process intensification tool for the preparation of pharmaceutically relevant N-heterocycles
John W. Tomlin
Thesis Defense: 17 January 2024
Committee: B. Frank Gupton, Ph.D. (Advisor), Suzanne M. Ruder, Ph.D. (Chair), Heather R. Lucas, Ph.D., James K. Ferri, Ph.D., Matthew C.T. Hartman, Ph.D.
A dissertation submitted in partial fulfillment of the requirements of Doctor of Philosophy at Virginia Commonwealth University
© 2024 John W. Tomlin Jr All Rights Reserved
Abstract
Essential medicines must be produced in large quantities to accommodate large global demand. The preparation of these active pharmaceutical ingredients (API) must therefore strive to be both cost-effective and accessible in terms of reactor and safety requirements in order to be manufactured and distributed as broadly as possible to ensure maximum impact. The growing field of continuous flow manufacturing offers incomparable benefits towards the synthesis of API in terms of unit operation complexity, energy efficiency, scalability, safety, and reproducibility under steady state conditions. By leveraging continuous flow’s inherent advantages in a multitude of reaction engineering elements, API can be prepared at a reduced cost with a reduction in environmental footprint through waste reduction, improved safety profiles, and increased material throughput. For these reasons, flow modalities have been implemented in the synthesis of three API in high levels of global demand: ciprofloxacin, tenofovir, and remdesivir. Additionally, a novel approach to the preparation of N-cyano aziridines is disclosed utilizing a heterogeneous catalyst in a packed bed reactor (PBR). This reaction leverages the advantages PBR offer in terms of metal-surface level interactions to enable access to these aziridines. Through the use of a PBR these N-cyano aziridines were accessed without the use of cyanogen azide, significantly improving operator safety in the preparation of these materials. Early results for the one-pot ring-opening of these N-cyano aziridines are disclosed as well.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-11-2024