A reaction screen in flowing solvent
Chemists charged with manufacturing pharmaceuticals have recently been exploring the efficiency advantages of continuous flow techniques. Perera et al. now show that a flow apparatus can also accelerate reaction optimization earlier in the drug discovery process. They modified a high-performance liquid chromatography system to screen a wide variety of solvent, ligand, and base combinations to optimize carbon-carbon bond formation. Injecting stock solution aliquots of the catalyst and reactants into a carrier solvent stream let the authors vary the main solvent efficiently and scale up the optimal conditions for product isolation.
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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.
Materials and Methods
Figs. S1 to S24
Tables S1 to S3
Data File S1
Correction (30 January 2018): The screening volume cited in (6) was corrected from 20 to 1000 nl.
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Volume 359 | Issue 6374
26 January 2018
26 January 2018
Copyright © 2018, The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Received: 8 September 2017
Accepted: 13 December 2017
Published in print: 26 January 2018
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We thank L. Bernier, J. Braganza, M. Collins, K. Dress, J. Lafontaine, G. Ng, U. Reilly, D. Richter, T. Long, G. Steeno, C. Subramanyam, and D. Truong for helpful discussions. D. P. was supported by postdoctoral research fellowship from Pfizer. Additional data supporting the conclusion are available in the supplementary materials.
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