Organic Process Research & Development
Article
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Figure 7. Claisen optimization scale out. 150 mL of material was
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problems. The new system was shown to provide consistent
performance using various sample extraction protocols such as
overfill and serial-overfill loop methods. Physical connectivity of
the MACOS reactor to the system analytics and the ability to
electronically actuate all modules including all sampling devices
(e.g., the sampling valve, the liquid handling station, and the
analyte transfer pump) allowed us to test our system for
automation, a step toward ultimately building a PAT-enabled
process tool for a variety of chemical applications. Develop-
ments are underway toward a more comprehensive optimiza-
tion model incorporating an array of CPPs and qualifiers for an
in-depth analysis of the process CQAs.
ASSOCIATED CONTENT
* Supporting Information
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S
Complete MACOS reactor design and layout, reagent delivery,
reactor, heat exchangers, analytics, communication and control,
experimental details of Claisen rearrangement, and references.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
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(13) For the seminal development of the MACOS reactor concept
and some applications in synthetic chemistry, see: (a) Comer, E.;
Organ, M. G. J. Am. Chem. Soc. 2005, 127, 8160−8167. (b) Organ, M.
G.; Comer, E. Chem.Eur. J. 2005, 11, 7223−7227. (c) Bremner, S.;
Organ, M. G. J. Comb. Chem. 2007, 9, 14−16.
Notes
The authors declare no competing financial interest.
(14) For the use of MACOS technology in multi-step natural product
synthesis, see: Achanta, S.; Liautard, V.; Paugh, R.; Organ, M. G.
Chem.Eur. J. 2010, 16, 12797−12800.
ACKNOWLEDGMENTS
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This work was supported by NSERC (Canada) and Eli Lilly
and Company through the Lilly Research Award Program
(LRAP). K.S. would like to thank the NSERC CREATE
Program in Microfluidic Applications and Training in
Cardiovascular Health (MATCH). The authors would like to
thank Tom Flug (CTC Analytics) for his guidance with the
sync signals and Darren Johnston (Bruker Canada) for his help
with the sequence integration.
(15) For applications of MACOS technology in medicinal chemistry
applications, see: (a) Zang, Q.; Javed, S.; Ullah, F.; Zhou, A.;
Knudtson, C. A.; Bi, D.; Basha, F. Z.; Organ, M. G.; Hanson, P. R.
Synthesis 2011, 2743−2750. (b) Hanson, P. R.; Organ, M. G.; Rolfe,
A.; Samarakoon, T. B.; Ullah, F. J. Flow Chem. 2011, 1, 32−39.
(c) Rolfe, A.; Ullah, F.; Samarakoon, T. B.; Kurtz, R. D.; Porubsky, P.;
Neuenswander, B.; Lushington, G. H.; Santini, C.; Organ, M. G.;
Hanson, P. R. ACS Combin. Sci. 2011, 13, 653−658. (d) Zang, Q.;
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dx.doi.org/10.1021/op5002512 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX