Communication
Green Chemistry
An ICP-MS analysis was performed14 on the final product
sonidegib 11 to determine the amount of residual Pd in this
material (Fig. 3). As expected, with these low levels of Pd
required for this SM coupling, essentially none was detected,
well below the strict FDA regulations of 10 ppm Pd per dose.15
article/releases/senhwa-biosciences-silmitasertib-basal-cell-
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Y. Jiang, J. Tsao, F. Sun, A. C. Pferdekamper, S. Dodd,
T. Tuntland, W. Maniara, J. F. Kelleher III, Y. M. Yao,
M. Warmuth, J. Williams and M. Dorsch, ACS Med. Chem.
Lett., 2010, 1, 130; (b) W. Gao, J. Jiang, Y. Wan, D. Cheng,
D. Han, X. Wu and S. Pan, WO2008/154259A1, 2007;
(c) C. Dierks, M. Warmuth and X. Wu, WO2008154259A1,
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Fig. 3 Residual palladium in synthesized sonidegib.
Conclusions
In summary, an efficient and sustainable route for the syn-
thesis of sonidegib has been developed. All reactions can be
performed under aqueous micellar conditions using a com-
mercially available and inexpensive surfactant. The synthesis
could be performed on a gram scale, using a minimum
number of pots, and avoiding column chromatography
without sacrificing chemical yields. Furthermore, it has been
shown that through Route 2, late stage Suzuki–Miyaura coup-
ling of highly functionalized intermediates could be per-
formed using only ppm levels of an inexpensive Pd catalyst
generated in situ from a common palladium(II) salt and tri-
phenylphosphine as ligand.
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Conflicts of interest
There are no conflicts to declare.
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We thank the NSF (18-56406) for financial support.
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6262 | Green Chem., 2019, 21, 6258–6262
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