(507b) On-Demand Medicinal Chemistry and Compound Synthesis in Oscillating Droplets

There is increasing pressure in drug discovery to deliver a steady stream of active compounds for physicochemical profiling and potency testing. In order to accelerate lead optimization, it is imperative to reduce the time required for each iteration of design, synthesis, and screening [1]. With recent advances in automation and high-throughput biological screening, the bottleneck has crept toward the synthesis step [2, 3, 4]. Medicinal chemistry laboratories have also benefitted from this trend in automation [5, 6, 7, 8], where one integrated platform has even been used for the discovery of novel AbI kinase inhibitors [9].

Here, we describe an automated chemistry platform that can efficiently screen a wide range of reactions, including single/multi-phase, single/multi-step, and photochemical reactions at the 20 microliter scale. Individual droplets are prepared by a liquid handler and moved through fluoropolymer tubing by a carrier gas at elevated pressures. Reactions occur in a heated reactor where the liquid droplet is oscillated back and forth to ensure thorough mixing – even for biphasic liquid-liquid reactions or liquid-gas reactions – without being limited to a finite residence time [10]. Optional inlet and/or outlet injections enable multistep chemistry. A portion of the crude product mixture is sampled and sent directly to an online HPLC/MS for analysis, purification, and product collection, typically of 10-500 μg.

The system offers the enhanced heat and mass transfer characteristics, increased safety, and opportunity for automation associated with flow chemistry while enabling the following key advantages: (a) reduction of material consumption, preparing just 40 microliters for each reaction condition, (b) elimination of residence time dispersion, (c) elimination of the inverse relationship between residence time and mass transfer rate for a flow reactor of fixed length, (d) simplification of continuous and discrete variable screening through the use of a liquid handler to prepare reaction mixtures, and (e) elimination of the time- and material-waste associated with waiting for flow reactors to reach steady state.

Importantly, because the reaction droplet is equivalent to one segment in a continuous segmented flow, reaction conditions identified using the platform can be directly translated to a continuous synthesis. This helps bridge the connection between the early research stages of drug discovery and the later stages, where material demands grow from the μg-mg scale to the g-kg scale.

As a demonstration of this platform, 36 examples of frequently used N-X bond forming reactions using typical small-molecule building blocks are screened. A representative biphasic Suzuki-Miyaura cross coupling reaction, a multi-step synthesis of the drug product diclofenac, and several visible-light catalyzed oxidations are also reported.

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