A Continuous Flow Sulfuryl Chloride Based Reaction – Synthesis of a Key Intermediate in a New Route Toward Emtricitabine and Lamivudine

• Juliana M. de Souza
• Mateo Berton
• David R. Snead*
• D. Tyler McQuade

• Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, 23284-3068, USA.

We demonstrate a continuous two-step sequence where a sulfenyl chloride is formed, trapped by vinyl acetate and chlorinated further via a Pummerer rearrangement. This sequence produces a key intermediate in our new approach to the oxathiolane core used to prepare the anti-retroviral medicines Emtricitabine and Lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm, temperature and pressure sensitivity, and evolution of hydrogen chloride and sulfur dioxide. These reactions are ideal candidates for implementation in a continuous, mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein, we discuss the flow implementation and the final reactor design that led to a 141g/h throughput system.

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