Organic Process Research & Development
Article
Xu, L.-W.; Li, J.-W.; Xia, C-G; Zhou, S-L; Hu, X.-X. Synlett 2003, 15,
2425.
(5) Warawa, E. J.; Campbell, J. R. J. Org. Chem. 1974, 39, 3511.
(6) The process was initially investigated on the racemic series to
establish proof of concept and to provide samples of the racemic series
for analytical development.
(7) Zaidlewicz, M.; Pakulski, M. M. Reduction of carbonyl groups:
transfer hydrogenation, hydrosilylation, catalytic hydroboration, and
reduction with borohydrides, aluminum hydrides, or boranes. In
Science of Synthesis, Stereoselective Synthesis; De Vries, J. G., Molander,
G. A., Evans, P. A., Eds.; Georg Thieme Verlag: Stuttgart, 2011; Vol. 2,
pp 59−131.
(8) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002, 67, 1712.
(9) Mukherjee, S.; Corey, E. J. Aldrichimica Acta 2010, 43, 49.
(10) A biocatalytic asymmetric reduction performed by Francois
Voelker, Laure Landric Burtin, and Hubert Picard in Vitry, France,
showed positive results but was not pursued due to timeline
constraints.
(11) We initially used the R-CBS catalyst providing S-4 due to the
availablility in laboratories and to provide a route to samples of all of
the stereoisomers of intermediates for ee determinations.
(12) Burkhardt, E. R.; Matos, K. Chem. Rev. 2006, 106, 2617.
(13) Atkins, W. J.; Burkhardt, E. R.; Matos, K. Org. Process Res. Dev.
2006, 10, 1292.
(14) Initial experiment following Overman protocol (see reference 3)
used NaH for proof of concept. Conditions: alcohol rac-4 was treated
with NaH (0.1 equiv) and trichloroacetonitrile (1.0 equiv) in THF at 0
°C; solvent was exhanged to xylene and heated to 140 °C; crude
product isolated in 93% yield.
(15) Imidate ester 11 has an exothermic onset with an energy of 789
kJ/kg at 113 °C that was subsequently shown to be the energy
generated from the rearrangement and not from decomposition.
Trichloroacetamidate 5 as the free base shows no exothermic thermal
activity under isothermal conditions at 120 °C for 30 h. The solvent
provides an additional barrier to any catastrophic decomposition.
Thus, the reaction is considered safe to scale up.
(16) Ru level was approximately 700 ppm in alcohol R-4, 100 ppm in
isolated S-5 without filtration, and 20 ppm in isolated S-5 with
filtration.
(17) Ru levels were lowered by charcoal treatment and/or plug
chromatography to <20 ppm.
(18) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188.
(19) Excess TCAN is believed to lead to the consumption of the base
through dimerization- or trimerization types of processes that lead to a
less basic media, thus prompting side reactions.
(20) The use of dichloromethane to improve selectivity in directed
hydrogenations has been reported: Brown, J. M. Angew. Chem., Int. Ed.
Engl. 1987, 26, 190. Brown, J. M.; Hall, S. A. Tetrahedron 1985, 41,
4639.
(21) MeOH is known to be a notoriously dangerous solvent for
hydrogenation reactions, but a thorough process safety review was
performed before proceeding.
(22) The physical quality aspects of drug substance 1 will be reported
in due course.
(23) For leading references for organocatalysis using cinchona-
derived organocatalysts, see: Song, C. E., Ed. Cinchona Alkaloids in
Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis;
Wiley-VCH: Weinheim, 2009.
(24) The stereochemistry of R-4 was assigned to be Z-isomer, see
reference 5. Isomerization of the Z-isomer to the E-isomer occurs
when the solution of the Z-isomer is exposed to light or acid
conditions; see: Klimova, T.; Garcia, M. M. J. Organomet. Chem. 1998,
559, 43.
purity, 99.9 wt %% purity with <0.05% achiral impurities and
<0.10% chiral impurities) as the desired polymorph: IR 1670
cm−1; 1H NMR (DMSO-d6) δ 10.68 (s, 1), 9.93 (s, 1), 7.63 (d,
1, J = 8.3), 7.55 (d, 1, J = 7.6), 7.45−7.35 (m, 3), 5.25 (dd, 1, J
= 8.9, 11.4), 4.08 (dt, 1, J = 4.7, 11.1), 3.78 (t, 1, J = 11.4), 3.61
(m, 1), 3.48 (m,1), 3.28 (m, 1), 2.27 (quint, 1, J = 3.1), 2.15
(m, 1), 2.03 (m, 1), 1.93 (m, 1), 1.82 (m, 1), 1.72 (m,1); 13C
NMR (DMSO-d6) δ 163.60, 137.51, 136.10 (2), 130.91, 129.07
(2), 128.96, 128.59, 128.50 (2), 128.02, 122.28, 58.60, 56.76,
49.29, 41.80, 29.08, 23.33, 22.54, 20.57 (Note: C−CF3 not
observed); 19F NMR δ 273, 5.1; LC−MS, m/z 457.14 [M +
H]. Anal. Calcd for C22H21Cl2F3N2O·HCl: C 53.51; H 4.49; N
5.67. Found: C 53.57; H 4.53; N 5.77.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra and HPLC chromotagrams for ee determinations
of intermediates. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Analytical Sciences Department at Sanofi
including Dirk Friedrich, Vince Morrison, Vasant Kumar, and
Li Liu for structural characterizations. We also acknowledge the
efforts of Boris Gordonov, Timothy Donegan, Harvey Lieber-
man, and Elizabeth Secord of the physical quality group for
aiding the understanding of the polymorph conversion.22
REFERENCES
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(1) Boulay, D.; Pichat, P; Dargazanli, G.; Estenne-Bouhtou, G.;
Terranova, J. P.; Rogacki, N.; Stemmelin, J.; Coste, A.; Lanneau, C.;
́
Desvignes, C.; Cohen, C.; Alonso, R.; Vige, X.; Biton, B.; Steinberg, R.;
Sevrin, M.; Oury-Donat, F.; George, P.; Bergis, O.; Griebel, G.;
Avenet, P.; Scatton, B. Pharmacol. Biochem. Behav. 2008, 91, 47.
Mohler, H.; Boison, D.; Singer, P.; Feldon, J.; Pauly-Evers, M.; Yee, B.
K. Biochem. Pharmacol. 2011, 81, 1065. Shim, S. S.; Hammonds, M.
D.; Kee, B. S. Eur. Arch. Psychiatry Clin. Neurosci. 2008, 258, 16.
(2) This report describes the second-generation synthesis of 1. A full
account of the development of the initial processes for scale-up will be
reported in due course and involves construction of the quinuclidine
core.
(3) For leading references to the Overman rearrangement, see:
Overman, L. E.; Carpenter, N. E. The Allylic Trihaloacetimidate
Rearrangement. In Organic Reactions; Overman, L. E., Ed.; John Wiley
& Sons, Inc: New York, 2005; Vol. 66, pp 3−107. Doherty, A. M.;
Kornberg, B. E.; Reily, M. D. J. Org. Chem. 1993, 58, 795. Overman, L.
E. Acc. Chem. Res. 1980, 13, 218. Anderson, C. E.; Overman, L. E. J.
Am. Chem. Soc. 2003, 125, 12412. See also: Chen, B.; Mapp, A. K. J.
Am. Chem. Soc. 2004, 126, 5364. Lee, E. E.; Batey, R. A. Angew. Chem.,
Int. Ed. 2004, 43, 1865. Fischer, D. F.; Xin, Z.-Q.; Peters, R. Angew.
Chem., Int. Ed. 2007, 46, 7704.
(4) For leading references for metal-catalyzed allylic aminations, see:
Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. Leitner,
A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093. Leitner, A.; Shu, C.;
Hartwig, J. F. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5830. Helmchen,
G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. Evans, P. A.; Robinson, J.
E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761. Flubacher, D.;
Helmchen, G. Tetrahedron Lett. 1999, 40, 3867. For Michael additions
to enones, see also: Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
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