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Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals

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Science  19 Jan 2018:
Vol. 359, Issue 6373, pp. 314-319
DOI: 10.1126/science.aao3466
  • Fig. 1 Schematic representation of the translation of a multistep synthesis from conception through to implementation as a reaction cartridge.

    Reactions necessary for the synthesis are identified (A→B→C→D, top left panel) and the specific chemical and physical processes and reaction parameters necessary for each reaction are laid out (conditions i. – iii., left panel). These processes are then translated into bespoke reaction modules designed to accomplish one or more of the chemical processes identified in the previous step (top right panel). The modules are then designed as 3D CAD models (lower center panel), with libraries of module components to accommodate the required reaction parameters. These digital models can then be fabricated to produce either a modular or monolithic implementation (lower right panel) of the process.

  • Fig. 2 Comparison of glass reactors with plastic reactionware for the optimized synthetic routes to (±)-baclofen (top), lamotrigine (middle), and zolimidine (bottom) with reaction yields for each step (reaction yields in PP vessels given in parentheses).

    Single (top right) or double (bottom right) chambered polypropylene reaction test cartridges were used. PP, polypropylene; TBAF, tetrabutylammonium fluoride; THF, tetrahydrofuran.

  • Fig. 3 Parameterized approach to the design of individual process modules.

    Digital libraries of module components (top) can be easily assembled to produce a wide range of module geometries dictated by the specific process and reaction parameters (e.g., solvent volumes, number of inputs and outputs, etc.) (bottom). Hydrophobic filters for phase separation are shown in red, and fritted glass filters are shown in blue. DCM, dichloromethane. HR, reactor height.

  • Fig. 4 Synthesis of (±)-baclofen in a series reaction cartridges.

    (Top) Conceptual synthetic procedure for the synthesis of (±)-baclofen under the conditions described in Fig. 2, showing the necessary processing sequence to effect this synthetic pathway. These processes were then split into modules (a) to (e) (indicated by gray boxes in the process sequences), which we translated into a digital design (middle left) and finally fabricated as either a modular (middle right) or monolithic (bottom left) implementation. A partially fabricated monolithic cartridge is also shown indicating the placement of non-3D printed components and internal fluidic pathways (bottom center and right). Both modular and monolithic cartridges are shown with Luer taper–compatible valving for interfacing with external fluidic inputs and pressure or vacuum lines.

Supplementary Materials

  • Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals

    Philip J. Kitson, Guillaume Marie, Jean-Patrick Francoia, Sergey S. Zalesskiy, Ralph C. Sigerson, Jennifer S. Mathieson, Leroy Cronin

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    • Materials and Methods 
    • Figs. S1 to S12 
    • References 

    Images, Video, and Other Media

    Movie S1
    This cartoon animation depicts the passage of the reagents and operations that are automatically carried out within the digitally defined reactionware cartridge as the operator adds the various reagents and follows the instructions for running the process, resulting in the production of the solid material at the end of the process.

    Additional Data

    Data S1
    Code S1
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