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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

Abstract

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

Summary

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

Resources

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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26
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30
A potential question arises as to whether the solvent used to make up the stock solution can influence the reaction. However, as demonstrated by Jouyban et al. (36), the impact of a mixed solvent in terms of a dielectric constant is a weighted average of the mixed components. As such, the effect of injecting a different solvent into a 9/1 organic/aqueous mixture that is diluted out 1:100 will largely be negated so long as it is inert to the chemistry being screened. The validity of this argument is borne out by the fact that the scaled batch experiments work in a similar manner to the flow experiments even without the solvents used to make up the stock solutions. However, although no effect of the small amount of stock solvent present in the reaction system has been observed thus far, we cannot preclude its potential involvement in all transformation screening.
31
The monomer 5 was used in 13 in-house library campaigns all involving Pd-mediated couplings (9 were Suzuki-Miyaura couplings whereas the remainder were Buchwald-Hartwig reactions). In none of the examples evaluated did 5 lead to any of the desired product in the library matrix.
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Information & Authors

Information

Published In

Science
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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Acknowledgments

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.

Authors

Affiliations

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.

Notes

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

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