Authors:Michael S. Placzek, Jessica M. Chmielecki, Connor Houghton, Alyssa Calder, Charlotte Wiles and Graham B. Jones
Continuous-flow methodologies have been applied to the synthesis of a number of fluorinated alkynyl arenes and heteroarenes. Through a series of optimizations reagent stoichiometry and reaction time were improved and substrate specificity was interrogated. Using optimized conditions under copper-free Sonogashira type couplings readily available arene building blocks were derivatized with fluoroalkynyl side chains in <10 min. Given the rapidity of the process and the enhanced purity profile of the products an immediate application of the work is in the development of 18F labeled versions of the agents for subsequent use in positron emission tomography (PET) imaging. A homolog of the Alzheimer's disease imaging agent Fallypride® was prepared using the methodology and additional analogs was identified.
Authors:Meaghan M. Sebeika, Nicholas G. Gedeon, Sara Sadler, Nicholas L. Kern, Devan J. Wilkins, David E. Bell and Graham B. Jones
Interest in the field of antibody—drug conjugates (ADCs) has grown exponentially over the past decade. As the product pipeline grows, there is increasing need for robust chemistries which allow selective and efficient functionalization of the antibody cores for introduction of appropriate linkers and spacer groups. Under conventional bioconjugation conditions, product heterogeneity often results, and the drug-to-antibody ratios (DAR) are inconsistent. Based on our experience in protein derivatization, we have investigated the potential for continuous-flow microreactor technology to expedite and facilitate such processes. We demonstrate its potential using reagent proteins and the chimeric monoclonal antibody infliximab (Remicade™).
Authors:Sara Sadler, Meaghan M. Sebeika, Nicholas L. Kern, David E. Bell, Chloe A. Laverack, Devan J. Wilkins, Alexander R. Moeller, Benjamin C. Nicolaysen, Paige N. Kozlowski, Charlotte Wiles, Robert J. Tinder and Graham B. Jones
A facile and benign route to N-heterocycles, including triazoles and triazolopyrimidines, has been developed. Using continuous-flow microreactor technology, organic azides are prepared in situ and reacted with cyanoacetamide in a [3+2] cycloaddition to produce a variety of substituted 1,2,3-triazoles, which can be elaborated into useful building blocks. A benzyl-substituted triazole was further functionalized to an analog of the core structure of the antiplatelet agent Brilinta®. The methodology lends itself well to flow chemistry, where reaction volumes are minimized, heating and mixing are consistent, and the need for intermediate azide isolation bypassed. The scope of the process is wide, and the efficiency is high, suggesting this as a practical, green route for the production of triazolo-based heterocycles.