An Automated Purification Workflow Coupled with Material-Sparing High-Throughput 1H NMR for Parallel Medicinal Chemistry.

Abstract

In medicinal chemistry, purification and characterization of organic compounds is an ever-growing challenge, with an increasing number of compounds being synthesized at a decreased scale of preparation. In response to this trend, we developed a parallel medicinal chemistry (PMC)-tailored platform, coupling automated purification to mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) on a range of synthetic scales (∼3.0-75.0 μmol). Here, the generation and acquisition of 1.7 mm NMR samples is fully integrated into a high-throughput automated workflow, processing 36 000 compounds yearly. Utilizing dead volume, which is inaccessible in conventional liquid handling, NMR samples are generated on as little as 10 μg without consuming material prioritized for biological assays. As miniaturized PMC synthesis becomes the industry standard, we can now obtain quality NMR spectra from limited material. Paired with automated structure verification, this platform has the potential to allow NMR to become as important for high-throughput analysis as ultrahigh performance liquid chromatography (UPLC)-MS.