End-to-End Automated Synthesis of C(sp3)‑Enriched Drug-like Molecules via Negishi Coupling and Novel, Automated Liquid–Liquid Extraction

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated seq...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2023-01, Vol.66 (1), p.716-732
Main Authors: Abdiaj, Irini, Cañellas, Santiago, Dieguez, Alejandro, Linares, Maria Lourdes, Pijper, Brenda, Fontana, Alberto, Rodriguez, Raquel, Trabanco, Andres, Palao, Eduardo, Alcázar, Jesus
Format: Article
Language:English
Subjects:
Chromatography, High Pressure Liquid
Humans
Indicators and Reagents
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Summary:Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)­aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid–liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01646