Managing the Workflow of a High-Throughput Organic Synthesis Laboratory: A Marriage of Automation and Information Management Technologies

Abstract

The production of high quality, individually characterized libraries of compounds requires a well-developed strategy, along with robust, user-friendly data and automation systems to support this strategy. We developed a workflow process to improve the efficiency of producing greater than 50,000 individual compounds per year. Our workflow process eliminates bottlenecks in traditional procedures and thus ensures a steady, predictable compound production rate. Initially, virtual library creation allowed for the determination of the physio-chemical properties of libraries as well as the ability to calculate the needed amounts of reagents and solvents for a production campaign. At this point, we registered all samples into our library database. Production of libraries began with loading the appropriate linkers onto resins, followed by complete characterization of the resin-linker intermediate. The resins were then loaded into IRORI MiniKans™ and sorted using the IRORI Autosort™ 10Kx sorting workstation. Chemistry was then performed using standard laboratory glassware. Additional sorting and chemistry steps were then performed until the compound was ready for cleavage off of the resin. The MiniKans were then sorted into Bohdan MiniBlocks™ and treated with the appropriate cleavage cocktail. Collection into 48-position racks was followed by removal of cleavage solution through vacuum centrifugation. The concentrate was then dissolved in a solvent mixture that allowed for standard liquid handling automation to create 96 well plates for analysis by high throughput flow inject NMR and LC/MS. Compounds 80% pure by LC/MS and presenting a >80% overall yield, as determined by NMR, were automatically flagged “acceptable” in the database. Compounds that failed to pass these analytical criteria were flagged “fail” in the database and were examined for trends that could be corrected in future library production. Finally, acceptable compounds were reformatted from the original source plates into master plates.