Organic Process Research & Development
Communication
MHz, DMSO-d6): δ (ppm) 11.64−11.40 (s, 1H), 7.74−7.49
(d, J = 8.1 Hz, 1H), 7.48−7.32 (t, J = 7.9 Hz, 2H), 7.32−7.22
(d, J = 8.3 Hz, 2H), 7.24−7.11 (t, J = 7.3 Hz, 1H), 6.33−6.21
(s, 1H), 6.21−6.06 (m, 2H), 5.62−5.52 (dd, J = 8.1, 1.7 Hz,
1H), 4.95−4.68 (hept, J = 6.2 Hz, 1H), 4.50−4.35 (dd, J =
11.4, 3.7 Hz, 1H), 4.35−4.20 (m, 1H), 4.17−4.01 (d, J = 9.2
Hz, 1H), 3.92−3.67 (ddt, J = 24.4, 10.0, 7.0 Hz, 2H), 3.39−
3.24 (s, 1H), 1.50−1.31 (s, 3H), 1.31−1.19 (d, J = 7.1 Hz,
3H), 1.18−1.05 (dd, J = 8.5, 6.4 Hz, 6H). 13C NMR (125
MHz, DMSO): δ 172.61, 172.57, 162.62, 150.69, 150.64,
150.50, 129.68, 124.55, 119.90, 119.86, 102.06, 80.03, 77.73,
72.34, 67.99, 63.59, 49.68, 22.37, 21.33, 21.28, 19.74, 19.69.
LC-MS calcd for C22H30ClN3O9P [M + H]+ m/z: 546.14.
Found: 546.2.
ACKNOWLEDGMENTS
■
The authors would like to thank Aaron Moment, Morgan
Crawford, and Darryl Chang for discussions and experimental
contributions. We thank Ryan Cohen and Rose Mathew for
help with impurity characterization. We thank Rebecca Ruck,
Paul Bulger, Neil Strotman, and L.-C. Campeau for proof-
reading suggestions.
ABBREVIATIONS USED
■
V = volume
LCAP = HPLC/UPLC area percentage
IY = isolated yield
AY = assay yield
REFERENCES
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
NMR characterization of specified impurities is provided
along with spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
́
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Zhuqing Liu − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
Steven M. Silverman − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
́
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Authors
Artis Klapars − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Bryon Simmons − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Ana Bellomo − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Alexei Kalinin − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Mark Weisel − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Jerry Hill − Department of Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
(5) (a) Uchiyama, M.; Aso, Y.; Noyori, R.; Hayakawa, Y. J. Org.
Chem. 1993, 58, 373. (b) Ross, B. S.; Ganapati Reddy, P.; Zhang, H.
(6) Simmons, B.; Liu, Z.; Klapars, A.; Bellomo, A.; Silverman, S. M.
2017, 19, 2218.
(7) This decision was made after taking into account both the
reaction purity profiles observed with each reagent and the ability to
implement a process on the anticipated commercial scale. While some
reagents appeared comparable to Me2AlCl in terms of reaction profile,
Complete contact information is available at:
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
F
Org. Process Res. Dev. XXXX, XXX, XXX−XXX