Journal ArticleDOI
Late‐Stage Functionalization and Characterization of Drugs by High‐Throughput Desorption Electrospray Ionization Mass Spectrometry
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In this paper , the potential value of high-throughput desorption electrospray ionization mass spectrometry (HT DESI-MS) for small-scale rapid late-stage functionalization (LSF) is investigated.Abstract:
Late-stage functionalization (LSF) of drug molecules is an approach to generate modified molecules that retain functional groups present in the active drugs. Here, we report a study that seeks to characterize the potential value of high-throughput desorption electrospray ionization mass spectrometry (HT DESI-MS) for small-scale rapid LSF. In conventional route screening, HT-based DESI-MS provides contactless, rapid analysis, reliable and reproducible data, minimal sample requirement, and exceptional tolerance to high salt concentrations. Ezetimibe (E), an established hypertension drug, is targeted for modification by LSF. C-H alkenylation and azo-click reactions are utilized to explore this approach to synthesis and analytical characterization. The effect of choice of reactant, stoichiometry, catalyst, and solvent are studied for both reactions using high throughput DESI-MS experiments. Optimum conditions for the formation of LSF products are established with identification by tandem mass spectrometry (MS/MS). read more
Citations
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Simultaneous and Spontaneous Oxidation and Reduction in Microdroplets by the Water Radical Cation/Anion Pair
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Accelerated and Concerted Aza‐Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High‐Throughput Formats
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Journal ArticleDOI
Simultaneous and Spontaneous Oxidation and Reduction in Microdroplets by the Water Radical Cation/Anion Pair
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References
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Journal ArticleDOI
C-H bond activation enables the rapid construction and late-stage diversification of functional molecules
TL;DR: This Perspective highlights the potential of metal-catalysed C-H bond activation reactions, which now extend beyond the field of traditional synthetic organic chemistry, and are more atom- and step-economical than previous methods.
Journal ArticleDOI
Ambient Mass Spectrometry
TL;DR: In DESI as discussed by the authors, electrically charged droplets are directed at the ambient object of interest; they release ions from the surface, which are then vacuumed through the air into a conventional mass spectrometer.
Journal ArticleDOI
The medicinal chemist's toolbox for late stage functionalization of drug-like molecules
TL;DR: This review details a toolbox of intermolecular C-H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations.
Journal ArticleDOI
Nanomole-scale high-throughput chemistry for the synthesis of complex molecules
Alexander Buitrago Santanilla,Erik L. Regalado,Tony Pereira,Michael Shevlin,Kevin P. Bateman,Louis-Charles Campeau,Jonathan Schneeweis,Simon Berritt,Zhi-Cai Shi,Philippe G. Nantermet,Yong Liu,Roy Helmy,Christopher J. Welch,Petr Vachal,Ian W. Davies,Tim Cernak,Spencer D. Dreher +16 more
TL;DR: An automated dosing and characterization protocol for optimizing chemical reaction conditions on the microgram scale is presented, which allowed them to screen numerous base and ligand combinations for catalytic C-N bond-forming reactions between complex pairs of compounds, in short supply, that resisted standard coupling conditions.
Journal ArticleDOI
Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis
Daniel A. DiRocco,Kevin D. Dykstra,Shane W. Krska,Petr Vachal,Donald V. Conway,Matthew T. Tudge +5 more
TL;DR: The use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles makes this method an important tool for drug discovery.
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