An Automated Microwave-Assisted Synthesis Purification System for Rapid Generation of Compound Libraries

Abstract

A novel methodology for the synthesis and purification of drug-like compound libraries has been developed through the use of a microwave reactor with an integrated high-performance liquid chromatography-mass spectrometry (HPLC-MS) system. The strategy uses a fully automated synthesizer with a microwave as energy source and robotic components for weighing and dispensing of solid reagents, handling liquid reagents, capper/crimper of microwave reaction tube assemblies, and transportation. Crude reaction products were filtered through solid-phase extraction cartridges and injected directly onto a reverse-phase chromatography column via an injection valve. For multistep synthesis, crude products were passed through scavenger resins and reintroduced for subsequent reactions. All synthetic and purification steps were conducted under full automation with no handling or isolation of intermediates, to afford the desired purified products. This approach opens the way to highly efficient generation of drug-like compounds as part of a lead discovery strategy or within a lead optimization program.

A high-throughput synthesis of 1,2,4-oxadiazole and 1,2,4-triazole libraries in a continuous flow reactor

“…Previously, we have reported on our high-throughput chemistry efforts, using both batch chemistry, [5][6][7][8] as well as ow chemistry. 9 Over time, our platforms have evolved into fully automated synthesis-purication platforms designed to reduce the overall turnaround time for library synthesis from 7-10 days to 2-4 days.…”

High‐Throughput Reaction Screening with Nanomoles of Solid Reagents Coated on Glass Beads

“…ChemBeads behave chemically differently depending on the chemical reagents coated, but physically, all ChemBeads behave like the host material, the glass beads. Thus, we were able to dispense over 300 solid reagents effectively using one automated solid dispensing protocol on the Chemspeed, including catalysts, ligands, inorganic bases and reactants, regardless of their original physical and chemical nature. Importantly, reagents that are air‐ and moisture‐sensitive have been coated effectively.…”

A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation

“…High-throughput experimentation (HTE), the practice of running multiple chemical reactions in parallel, is routinely used in the pharmaceutical industry at various stages of the drug discovery process. − HTE and automated synthetic techniques such as robotic-enabled reaction setup can be used to generate screening sets to probe biological activity; these libraries can be created using a variety of methods, including the well-known split-pool combinatorial approach. − HTE can also be exploited to screen multiple reaction conditions in tandem in order to expedite route optimization for desired lead compounds . Although there are several ways that this approach can be applied to enable drug discovery and development, the success of any HTE campaign relies on the interplay between high-throughput reaction setup and analysis …”