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

Available for download on Saturday, April 11, 2026

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