DOI
https://doi.org/10.25772/DEA7-6T34
Author ORCID Identifier
https://orcid.org/0009-0002-4839-3694
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
B. Frank Gupton
Abstract
Rifapentine (RPT) is a critical antitubercular agent used in the treatment of both pulmonary and latent tuberculosis infections. In addition to ongoing RPT shortages, concerns have been raised by regulatory agencies regarding unacceptable levels of nitrosamine impurities in RPT, which are primarily introduced through key starting material 1-amino-4-cyclopentyl piperazine (ACP). A novel approach to ACP has been developed and is coupled with a continuous flow synthesis of RPT from the common starting material rifamycin S (rif S). A stable precursor to ACP, Cbz-ACP, is first prepared from benzyl carbazate in three linear steps. Facile deprotection of Cbz-ACP and subsequent reaction of ACP are both carried out in continuous flow to prevent aerial autooxidation to the nitrosamine. This synthesis is expected to be readily scalable and its compatibility with small continuous manufacturing units may help lower the barrier for entry for new manufacturers.
The structure of an intermediate commonly used in the preparation of RPT is disputed in the literature. The structure of this intermediate has been determined using NMR and corrections to the literature are proposed. A novel conformer of this intermediate is also reported and characterized.
Rights
© 2023 Erin E. Stryker All Rights Reserved
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-6-2023