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.
Science, this issue p. 429


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.

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Supplementary Material


Materials and Methods
Supplementary Text
Figs. S1 to S24
Tables S1 to S3
References (3740)
Data File S1


File (aap9112_data_file_s1.xlsx)
File (aap9112_perera_sm.pdf)
Correction (30 January 2018): The screening volume cited in (6) was corrected from 20 to 1000 nl.

References and Notes

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Information & Authors


Published In

Volume 359 | Issue 6374
26 January 2018

Submission history

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.



Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.


Corresponding author. Email: [email protected] (D.P.); [email protected] (P.R.); [email protected] (N.W.S.)

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