DOI
https://doi.org/10.25772/JQGX-BV59
Defense Date
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
Dr. Katherine Belecki
Second Advisor
Dr. B. Frank Gupton
Third Advisor
Dr. Vladimir A. Sidorov
Fourth Advisor
Dr. Julio C. Alvarez
Fifth Advisor
Dr. Keith C. Ellis
Abstract
Harnessing the power of process intensification principles in a robust synthesis of the anti-retroviral drug lamivudine (3TC)
Author: Sudhair A. K. James
Advisor: Dr. Katherine Belecki
Research Assistant Professor, Department of Chemistry
In current pharmaceutical practices, many synthetic routes of active pharmaceutical ingredients (APIs) evolved from processes targeting access to a variety of chemical analogs rather than waste reduction or green practices.1 Even after patent expiration, most innovator API processes continue to be carried forward in manufacturing strategies of other companies, contributing to elevated costs of many generic and global health drugs.2,3 Access to important medications is a pressing concern for developing countries, contributing to both local and global health crises. Implementing chemical innovations and process intensification strategies can generate more efficient and greener processes and in turn lower the overall drug cost, increasing access while also reducing the environmental impact of pharmaceutical manufacturing.4
Lamivudine (3TC) is a cytidine analog in which the ribose has been replaced by a chiral 1,3-oxathiolane moiety. It is a potent nucleoside drug targeting retroviral infections such as HIV-1 and HIV-2.5 Access to the desired cis-(−)-enantiomer presents a major synthetic challenge, due to the need for stereocontrol of two labile stereo centers and regioselective N-glycosylation methodologies. Several creative routes to gain access to enantiomerically pure synthons for this chiral portion of oxathiolane are well established. However, cytosine itself represents a major raw material cost component in commercial syntheses, and bulk cytosine pricing can be volatile. Moreover, pre-silylation of cytosine is a crucial step in the traditional procedures due to nucleophilicity of the exocyclic amine. We aimed to circumvent these problems with an alternative cytosine analog that can be incorporated directly and is available at a lower cost.
To test our hypothesis, we employed uracil as a potential alternative nucleophile under different base-mediated reaction conditions. We have successfully incorporated uracil directly into a chiral oxathiolane precursor without pre-silylation, followed by conversion into the corresponding cytosine analog in over 80% yield. In addition, we have optimized reaction conditions to increase the overall yield of different forms of chiral oxathiolane with minimal deviation from current manufacturing practices. An evaluation of this alternative route for cost-effectiveness and chemical efficiency will enable identification of the optimum route for increasing access to this important medication for populations in need.
(1) Federsel, H.-J. Chemical Process Research and Development in the 21st Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry Perspective. Acc. Chem. Res. 2009, 42 (5), 671–680. https://doi.org/10.1021/ar800257v.
(2) Dach, R.; Song, J. J.; Roschangar, F.; Samstag, W.; Senanayake, C. H. The Eight Criteria Defining a Good Chemical Manufacturing Process. Org. Process Res. Dev. 2012, 16 (11), 1697–1706. https://doi.org/10.1021/op300144g.
(3) Ott, D.; Kralisch, D.; Denčić, I.; Hessel, V.; Laribi, Y.; Perrichon, P. D.; Berguerand, C.; Kiwi-Minsker, L.; Loeb, P. Life Cycle Analysis within Pharmaceutical Process Optimization and Intensification: Case Study of Active Pharmaceutical Ingredient Production. ChemSusChem 2014. 7 (12), 3521-33. https://doi.org/10.1002/cssc.201402313.
(4) Verghese, J.; Kong, C. J.; Rivalti, D.; Yu, E. C.; Krack, R.; Alcázar, J.; Manley, J. B.; McQuade, D. T.; Ahmad, S.; Belecki, K.; Gupton, B. F. Increasing Global Access to the High-Volume HIV Drug Nevirapine through Process Intensification. Green Chem. 2017, 19 (13), 2986–2991. https://doi.org/10.1039/C7GC00937B.
(5) Quercia, R.; Perno, C.-F.; Koteff, J.; Moore, K.; McCoig, C.; St. Clair, M.; Kuritzkes, D. Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection. J. Acquir. Immune Defic. Syndr. 1999 2018, 78 (2), 125–135. https://doi.org/10.1097/QAI.0000000000001660.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-12-2022
Included in
Heterocyclic Compounds Commons, Medicinal and Pharmaceutical Chemistry Commons, Organic Chemicals Commons, Other Chemicals and Drugs Commons, Pharmaceutical Preparations Commons, Virus Diseases Commons