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A Continuous Flow Sulfuryl Chloride-Based ReactionSynthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
journal contribution
posted on 2020-05-19, 18:13 authored by Juliana
M. de Souza, Mateo Berton, David R. Snead, D. Tyler McQuadeWe demonstrate a continuous two-step
sequence in which sulfenyl
chloride is formed, trapped by vinyl acetate, and chlorinated further
via a Pummerer rearrangement. These reactions produce a key intermediate
in our new approach to the oxathiolane core used to prepare the antiretroviral
medicines emtricitabine and lamivudine. During batch scale-up to tens
of grams, we found that the sequence featured a strong exotherm and
evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous
byproducts in solution and controlling the temperature led to better
outcomes. 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 system with a 141 g/h throughput.
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lamivudineKey Intermediatechlorinatedsequenceflow implementationsolutionexothermLamivudinehydrogen chloridereactor designreagent additionstencandidateEmtricitabinebyproduct formationContinuousChloride-BasedSulfurylsulfenyl chlorideFlowbatch scale-upPummerer rearrangementHereinevolutionthroughputapproachmesoscale systemNew Routesakevinyl acetatesulfur dioxideoxathiolane coreoutcomeantiretroviral medicines emtricitabine
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