Many synthetic routes of active pharmaceutical ingredients (APIs) that are designed to access a variety of chemical analogs have limited regard for commercial consideration. Additionally, the innovator API processes are often still carried forward in manufacturing settings even after patent expiration, contributing to elevated costs of many generic and global health drugs and creating opportunities to address expensive starting materials and lengthy synthetic sequences. In developing countries, access to important medications can be limited for substantial portions of the population due to cost. Implementing chemical innovations and process intensification strategies can generate more efficient and greener processes while also helping to mitigate both local and global health crises.<br/><br/>Lamivudine (3TC) is a potent nucleoside drug targeting retroviral infections such as HIV-1 and HIV-2. It is a cytosine triphosphate analog in which the ribose has been replaced by a chiral 1,3-oxathiolane moiety. Access to the <i>cis</i>-(−)-enantiomer presents a major synthetic challenge, due to the need for stereo control of two labile stereocenters and regioselective N-glycosylation methodologies. Several creative routes have been reported in the literature to gain access to enantiomerically pure synthons for the chiral oxathiolane portion using L-menthol as a chiral auxiliary agent. The nucleophilicity of the exocyclic amine of cytosine makes pre-silyation a crucial step for glycosylation in these processes. We aimed to circumvent this problem with a cytosine analog that can be incorporated directly and is available at a lower cost. To test our hypothesis, uracil was examined as a potential nucleophile under different base-mediated reaction conditions. We have successfully glycosylated uracil with a chiral oxathiolane intermediate without pre-silylation, followed by conversion into the corresponding cytosine analog in over 80% yield. 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.

Applying process intensification principles to the anti-retroviral drug lamivudine (3TC) to improve global health access

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.