A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2018-01, Vol.359 (6374), p.429-434
Main Authors: Perera, Damith, Tucker, Joseph W, Brahmbhatt, Shalini, Helal, Christopher J, Chong, Ashley, Farrell, William, Richardson, Paul, Sach, Neal W
Format: Article
Language:English
Subjects:
Automation
Chemical reactions
Chemical synthesis
Chemists
Chromatography
Continuous flow
Data points
Drug discovery
Drugs
High performance liquid chromatography
High temperature
Inhalants
Intermediates
Liquid chromatography
Mass spectrometry
Mass spectroscopy
Modular systems
Modular units
Optimization
Pharmaceuticals
Screening
Solvents
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Summary:The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography-mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours. Through multiple injections of the same segment, the system directly produced micromole quantities of desired material. The optimal conditions were also replicated in traditional flow and batch mode at 50- to 200-milligram scale to provide good to excellent yields.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aap9112