Automated chemical synthesis carries great promises of safety, efficiency and reproducibility for both research and industry laboratories. Current approaches are based on specifically-designed automation systems, which present two major drawbacks: (i) existing apparatus must be modified to be integrated into the automation systems; (ii) such systems are not flexible and would require substantial re-design to handle new reactions or procedures. In this paper, we propose a system based on a robot arm which, by mimicking the motions of human chemists, is able to perform complex chemical reactions without any modifications to the existing setup used by humans. The system is capable of precise liquid handling, mixing, filtering, and is flexible: new skills and procedures could be added with minimum effort. We show that the robot is able to perform a Michael reaction, reaching a yield of 34 , which is comparable to that obtained by a junior chemist (undergraduate student in Chemistry).
Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (S N Ar), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus. Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.