Semisynthetic artemisinin, the chemical path to industrial production

Article abstract of DOI:10.1021/op4003196

A new commercial-scale alternative manufacturing process to produce a complementary source of artemisinin to supplement the plant-derived supply is described by of biosynthetic artemisinic acid into semisynthetic artemisinin using diastereoselective hydrogenation and photooxidation as pivotal steps. This process was accepted by Prequalification of Medicines Programme (PQP) in 2013 as a first source of nonplant-derived-artemisinin in industrial scale from Sanofi production facility in Garessio, Italy.l scale from Sanofi production facility in Garessio, Italy.

Full text of DOI:10.1021/op4003196

Article
pubs.acs.org/OPRD
Semisynthetic Artemisinin, the Chemical Path to Industrial
Production
Joel Turconi,*,† Frederic Griolet,† Ronan Guevel,‡ Gilles Oddon,§ Roberto Villa,∥ Andrea Geatti,∥
́
́
̈
Massimo Hvala,∥ Kai Rossen,⊥ Rudolf Goller,⊥ and Andreas Burgard*,⊥
̈
†Sanofi, Sisteron Plant, 45 chemin de Met
́ ́
eline, B.P. 15 Sisteron, France
‡Sanofi, Pasteur Campus, Merieux -1541, Avenue Marcel Merieux - 69280 Marcy L’Etoile, France
§Sanofi Chimie, 31-33 quai Armand Barbes
̀ ̂
, 69583 Neuville-sur-Saone cedex, France
∥Miglioram Processi, Sanofi-Aventis, Via Roberto Lepetit, 142, 12075 Garessio (CN), Italy
⊥Chemistry and Biotechnology Development, Frankfurt Chemistry, Sanofi-Aventis Deutschland GmbH, Industriepark Hochst,
̈
Building G 838, 65926 Frankfurt am Main, Germany
ABSTRACT: A new commercial-scale alternative manufacturing process to produce a complementary source of artemisinin to
supplement the plant-derived supply is described by conversion of biosynthetic artemisinic acid into semisynthetic artemisinin
using diastereoselective hydrogenation and photooxidation as pivotal steps. This process was accepted by Prequalification of
Medicines Programme (PQP) in 2013 as a first source of nonplant-derived-artemisinin in industrial scale from Sanofi production
facility in Garessio, Italy.
basis of the fundamental work of Acton, Roth4 and Brown, et
1. INTRODUCTION
Malaria is a disease that affects millions of people, mostly in
tropical and subtropical regions. The human and economic toll
al.5 the company Amyris managed to convert artemisinic acid
(AA) into artemisinin, and this laboratory synthesis gave for the
first time hope and guidance for a viable industrial process that
would allow the large-scale preparation of artemisinin
independent from the extractive process. The work of Keasling
and Amyris has recently been described6 (Scheme 2), and we
will now detail the efforts undertaken at Sanofi in the years
2008−2013 to turn these initial results into a fully implemented
industrial process that is resulting in 35 t of artemisinin in 2013,
increasing to 60 tons in 2014. This development work has been
supported by the Bill and Melinda Gates Foundation with the
goal of leading to a consistent source of artemisinin using a “no
profit, no loss” cost model for Sanofi. The implementation of
this process successfully addressed environmental, cost, safety,
quality, and regulatory aspects, both for the scale-up of the
fermentation of artemisinic acid (AA) and for its subsequent
conversion to artemisinin. The fermentation will be detailed in
a separate publication; this paper will focus on the steps
necessary to convert artemisinic acid (AA) to artemisinin, i.e.
the development of a homogeneously catalyzed highly
diastereoselective hydrogenation, a photochemical singlet
oxygenation, and a subsequent complex rearrangement
clearly all serious challenges, especially keeping in mind that
artemisinin is a peroxide requiring a careful attention to safety
on scale. The synthetic sequence towards artemisinin as
implemented by Sanofi is thus an excellent example of
combining synthetic biology, homogeneous catalysis, and
photochemistry to achieve an efficient, large-scale access to
an important drug for a price that is at least competitive with a
simple extraction from the plant. Bearing major breakthroughs
is devastating, e.g. an estimated 300 million children are
infected every year, with often debilitating effects.1
A global effort is under way to fight malaria using
preventative measures and through vaccine development, but
also through the provision of cost-efficient treatment options.
Artemisinin and its derivatives (dihydroartemisinin, artemether,
artesunate) are essential to modern malaria therapy, thus
requiring an efficient access to these compounds (Scheme 1).
Scheme 1. Artemisinin and its derivatives
Guided by the knowledge of traditional medicine, artemisinin
was discovered, identified, and brought to the patient by
Chinese scientists at the beginning of the 1970s. Artemisinin is
found in the plant Artemisia annua, which contains highly
variable amounts in its leaves. Until recently, extraction
provided the only efficient access to artemisinin, which resulted
in large price fluctuations and therefore an unstable supply.2
A major break-through was the discovery by Keasling of a
biosynthetic pathway for the preparation of artemisinic acid
(AA), an advanced precursor of artemisinin, in yeast.3 On the
Received: November 11, 2013
Published: February 17, 2014
© 2014 American Chemical Society
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Scheme 2. Initial chemistry path by Amyris
Scheme 3. New generation process by Sanofi
in synthetic methodology, we are confident that this hybrid
approach is far superior to a total synthesis and none of the
many total syntheses published7−12 appear to even approach
providing a basis for a potentially viable process. The synthetic
sequence applied by Sanofi13,14 follows a strategy that is closely
related to the mechanism used by the Artemisia annua plant and
is summarized in Scheme 3.
described by Amyris6 as giving a near quantitative conversion
with surprisingly high 90:10 diastereoselectivity for the desired
stereochemistry. Combining the inherent diastereoselectivity of
artemisinic acid (AA) with an appropriately matched chiral
hydrogenation catalyst should allow for better selectivity. In
addition, the high loading required for the Wilkinson catalyst
and the high cost of Rh makes its use impractical for any
industrial production. Indeed, a comprehensive screen of
catalysts and ligands performed at Takasago for Sanofi provided
the RuCl2[(R)-DTBM-Segphos](DMF)n catalyst.20 At 22 bar
H2 a 95:5 selectivity is obtained, and even S/C levels of 8.000
give complete hydrogenation in a few hours. S/C levels of
16.000 are also successfully feasible but take more time
(Scheme 3). It is notable that a Ru phanephos catalyst performs
essentially identically, but none of the catalysts or systems
screened led to perfect diastereoselectivity. We recently
published in the literature a paper about a remarkably
diastereoselective hydrogenation of artemisinic acid (AA)
with diimide, which resulted in diastereoselctivities ≥97:3 and
excellent yields of >90% (including the crystallization, isolation,
and drying step). The implementation of this hydrogenation on
Interestingly, the Seeberger group15 recently described a
useful extension of this chemistry by performing the photo-
oxidation step in a full flow system, rather than in the semibatch
process that Sanofi implemented in the factory. The inherent
advantages of using flow chemistry, especially as applied to
photochemical reactions, are highlighted by other Seeberger
publications,16−19 pointing to potential future improvements.
2. DIASTEREOSELECTIVE HYDROGENATION
The first challenge is the diastereoselective hydrogenation of
the acrylate system of artemisinic acid (AA) to dihydroartemi-
sinic acid (DHAA). While it was known that this could be
achieved using, e.g., Ni borohydride in very moderate
diastereoselectivity (3:2), the use of Wilkinson catalyst was
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Scheme 4. New-generation process by Sanofi: proposed photooxidation mechanism
scale achieved the hydrogenation by using air and hydrazine
hydrate in an alcoholic solvent.21−23
several subsequent chemical steps (Hock cleavage, additional
oxygenation, ring closure) as illustrated in Scheme 4.
Fully cognizant of the issues, we decided to perform the
Schenck ene reaction in methylene chloride using tetraphe-
nylporphyrin (TPP) as a sensitizer. The choice of these classical
reaction conditions is dictated by safety concerns (non-
halogenated solvents are not compatible with the oxygenation
conditions) and implies significant capital investment to ensure
the complete containment and recycling of methylene chloride.
With these constraints, the use of methylene chloride is
environmentally acceptable. Tetraphenylporphyrin (TPP) is
not only readily available but also a highly efficient sensitizer for
the photochemical conversion of triplet oxygen to singlet
oxygen.
An additional constraint for devising a reaction sequence was
discovered when we examined the safety data for the initially
formed Schenck ene hydroperoxide. An exothermal decom-
position of the hydroperoxide of dihydroartemisinic acid at +15
°C ruled out any sequence that led to a significant accumulation
of this compound, particularly in the consideration that metallic
surfaces in the production equipment could accelerate the
decomposition of hydroperoxides. Consequently, the only
viable option to obtain the desired sequence would have to
implement a one-pot sequence from dihydroartemisinic acid
(DHAA), or a derivative thereof, to artemisinin, comprising at
least four distinct chemical steps. We examined dihydroarte-
misinic acid (DHAA) and several derivatives of dihydroarte-
misinic acid (DHAA) in this direct conversion, using TFA as an
acid. A reasonable working hypothesis as to the mechanism of
the final closure to the tricyclic system of artemisinin led us to
propose the use of activated esters (mixed anhydride)
accomplished by ethyl chloroformate/potassium carbonate in
the hope that these would facilitate the final ring closure. The
use of readily available mixed anhydrides leads to a much
cleaner and improved reaction, resulting in a highly satisfactory
overall yield of 55% isolated artemisinin from the starting
material artemisinic acid (AA) (i.e., comprising the diaster-
eoselective hydrogenation, the formation of the mixed
anhydride, and the final photochemical reaction sequence,
including the final isolation of artemisinin as a pure, crystalline
compound) as depicted in Scheme 3.
3. PHOTOOXIDATION TO ARTEMISININ
With dihydroartemisinic acid (DHAA) available, the subse-
quent conversion of dihydroartemisinic acid (DHAA) to
artemisinin involves complex oxidation/rearrangements. Mech-
anistically, it is assumed that a regioselective Schenck ene
reaction between singlet oxygen and the double bond takes
place, followed by a Hock cleavage and a subsequent
oxygenation and cyclization. This mechanistic sequence had
been proposed and supported with experimental evidence by
Brown5 and is also assumed to be the mechanism taking place
in Artemisia annua. In view of the complexity of the
transformations it is not surprising that numerous impurities
can and do arise. Initially, we followed the lead set by Amyris
and obtained the singlet oxygen in the Aubry decomposition of
H2O2 with molybdates24 and induced the subsequent Hock
cleavage with copper sulfonate salts. Gratifyingly, a yield as high
as 41% could be obtained for the complex sequence when
solvents and reaction conditions were carefully controlled.
However, all attempts to improve this yield failed, despite
significant efforts invested into the isolation and elucidation of
reaction impurities to allow a better understanding of the
reaction.
The utility of the Aubry reaction allows the generation of
singlet oxygen, and thus the Schenck ene reaction, while
avoiding the need for photochemical equipment. While in
principle highly attractive, photochemical reactions are rarely
practiced in industry25 and there is even less precedence for the
large-scale application of the Schenck ene reaction with
photochemically generated singlet oxygen. This is easily
understood, as the hurdles to the implementation of a large-
scale Schenck ene reaction are significant. Apart from the lack
of experience and equipment, the choice of permissible solvents
is very limited, the resulting products are inherently unsafe
hydroperoxides, and the chemical engineering aspects such as
mixing, gas transfer, and light transmission are unusually
complex on scale. In the case of the synthesis of artemisinin, the
situation is even more complex as the Schenck ene reaction is
just the beginning of a complex reaction cascade that requires
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Scheme 5. Manufacturing of semisynthetic artemisinin in production scale
On the basis of these results, a dedicated pilot unit was set up
at Sanofi facility, Neuville (France). We selected a semibatch
mode concept with a recirculation loop, which is possible as
artemisinin is very stable under the reaction conditions and it
offers optimal conditions versus energy consumption and the
transformation rate. In addition to the other chemical
engineering challenges, critical parameters included construc-
tion materials that minimize the loss of light (optimizing the
quantum photonic yield) and the choice of a lamp with the
optimal spectral distribution of emitted spectrum (medium-
pressure mercury/gallium lamp). The unit must also ensure a
good turbulence of the recirculating fluid and allow a good
gas−liquid transfer, while maintaining the internal temperature
at −10 °C.
for such a compound. Nevertheless, we managed to define a
safe operating range for the isolation and set up a strict safety
management process for the operation on scale. The first pilot
batch was successful at 50-kg scale in 2011 in Neuville (filter
dryer and centrifuge technologies).
4. INDUSTRIALIZATION
Of obvious critical importance is the compliance of the isolated
material with the required purity specifications. Prequalification
of Medicines Programme (PQP) announced the acceptability
of the first source of nonplant-derived-artemisinin, manufac-
tured by Sanofi, for use in manufacture of API submitted to
WHO in May 2013.26
A significant effort was dedicated to finding conditions that
allowed a safe and reliable isolation of crystalline artemisinin
from this reaction mixture; artemisinin is a peroxide with a
DSC onset temperature of 160 °C and a release of 840 J/g. To
this end, the reaction mixture has to be washed several times to
remove the TFA, using aq sodium bicarbonate, and filtered
over a specific absorbent to remove traces of tetraphenylpor-
phyrin (TPP). This treatment is mandatory as a safe solvent
switch to heptane for the isolation of crystalline artemisinin is
not trivial, and the development and implementation of a
reliably safe and reproducible isolation procedure is challenging
The ultimate goal of all process development activities is the
implementation of laboratory and pilot-plant results into
commercial equipment. Indeed, guided by the results from
the Neuville pilot plant, the investment into large-scale
equipment was undertaken at the Sanofi facility in Garessio,
Italy. The equipment and process were validated by 2012 and is
producing commercial quantities of artemisinin since 2013,
with 35 tons expected for 2013, ramping up to 60 tons in 2014
(batch size is on average 370 kg isolated artemisinin). On the
basis of the work described in part above, the material meets
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the quality and purity requirements for a drug and is being used
to make drug product (Scheme 5).
of artemisinin was added with 180 kg ethanol, and then it was
cooled at about 20 °C to accomplish the crystallization. The
wet product was isolated by centrifugation, and washed twice
with 1200 kg mixture of n-heptane/ethanol. The artemisinin
was dried under reduced pressure at a temperature not
exceeding 36 °C. About 370 kg of artemisinin as crystalline
white powder was typically obtained for a batch size of 600 kg
of artemisinic acid.
5. CONCLUSION
In summary, we can report the successful completion of a long
story: the sole reliance on artemisinin isolated from the plant
Artemisia annua can be supplemented by a reliable and
plannable supply chain that uses a combination of synthetic
biology, sophisticated homogeneous catalysis and complex
photochemistry to produce industrial quantities of an important
drug.
Analytical Data of Semisynthetic Artemisinin. Optical
Rotation: [α]20 = +74−78 [10 mg/mL in ethanol].
D
The melting point of the crystalline artemisinin was found to
be about 159 °C.
The theoretical mass of [M + H]+ is 283.1545 amu. The
high-resolution mass spectrum shows the [M + H]+ at m/z =
283.1557 amu. This measured mass is consistent with the [M +
H]+ formula C15H22O5 within an deviation of 4.2 ppm. (amu:
atomic mass unit)
6. EXPERIMENTAL SECTION
Step 1: Hydrogenation of Artemisinic Acid to
Dihydroartemisinic Acid (DHAA). Artemisinic acid (600
kg) was dissolved in 1200 kg methanol; 259 kg triethylamine
and 480 g ruthenium-Segphos catalyst were added. The
homogeneous mixture was hydrogenated using 22 bar at 25
°C to yield dihydroartemisinic acid as triethylammonium salt
dissolved in methanol. The hydrogenation was monitored by
HPLC. Dihydroartemisinic acid (DHAA) triethylammonium
salt solution was distilled under vacuum to remove methanol
before 2000 kg dichloromethane were added. Water (1800 kg)
was added to the dichloromethane solution of DHAA, and with
270 kg conc. hydrochloric acid, the pH of the aqueous phase
was adjusted until pH was 1−2. After phases were separated,
the organic phase was washed a second time with 2000 kg
water. The combined organic phases were treated with 30 kg
silica gel in order to remove ruthenium traces and were filtered
and directly used in the next step. The dihydroartemisinic acid
(DHAA) was not isolated before the next step.
Data acquisition of all NMR spectra was achieved using a
spectrometer operating at a proton resonance frequency of 600
MHz and a carbon 13 resonance frequency of 150 MHz (see
Table 1). The NMR spectra were recorded using a solution in
deuterated dimethyl sulfoxide (DMSO-d6). Calibration was
performed using the residual solvent signal.
Table 1. NMR spectral data
Step 2: Activation of Dihydroartemisinic Acid (DHAA)
with Ethylchloroformate to Mixed Anhydride
(DHAEMC). Potassium carbonate (410 kg) was added to the
dichloromethane solution of dihydroartemisinic acid before 306
kg ethylchloroformate was introduced to perform the reaction
at 20−30 °C to mixed anhydride (DHAEMC). The reaction
was monitored by HPLC. As soon as the reaction was
accomplished, 2230 kg water was added. After phase separation,
the organic phase was cooled at about −10 °C to remove
residual water as ice in the organic phase before the subsequent
photooxidation.
Step 3: Photooxidation of Mixed Anhydride
(DHAEMC) to Artemisinin. To the solution of DHAEMC
were added 2570 kg dichloromethane and 300 g tetraphe-
nylporphyrin (TPP) before the solution was exposed to light
irradiation using photoreactors containing mercury vapour
lamps and ambient air bubbling at about −10 to −15 °C. In the
beginning of the irradiation 132 kg trifluoroacetic acid was
added to the reaction mixture. The reaction was monitored by
HPLC. As soon as the reaction was completed, the solution was
treated twice with 720 L aqueous solution of sodium
bicarbonate and was subsequently washed with 1440 kg
water. The washed organic phase was treated with 30 kg
activated charcoal and filtered. Before the crystallisation step,
the ADT24h of the reaction mixture was checked.
a
b
assignment
13C [ppm]
C-type
1H [ppm]
mh
1
171.34
104.62
93.20
79.48
49.43
43.85
36.02
35.42
33.07
32.44
24.85
24.28
22.36
19.46
12.30
CO
C-quat.
CH
−
−
6.11
−
−
2
3
singlet
4
C-quat.
CH
−
−
5
1.34
1.79
1.54
multiplet
dt
6
CH
7
CH
multiplet
multiplet
multiplet
multiplet
singulet
multiplet
dq
8
CH2
CH2
CH
2.28, 2.06
1.65
9
10
11
12
13
14
15
3.17
CH3
CH2
CH2
CH3
CH3
1.36
1.34, 1.94
1.15, 1.73
0.93
doublet
doublet
1.08
a
b
Proton chemical shifts are given in approximations. The proton
multiplicities are annotated according to their obvious appearance in
the spectrum.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Andreas.Burgard@sanofi.com
*E-mail: Joel.Turconi@sanofi.com
■
Step 4: Crystallization of Artemisinin. By the organic
solution of artemisinin coming from the photooxidation,
dichloromethane was partially removed by distillation under
vacuum, while 2700 kg n-heptane was added in order to
maintain a constant volume in the reactor. During the solvent
switch artemisinin was crystallized. The n-heptane suspension
Notes
The authors declare no competing financial interest.
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(21) Feth, M. P.; Rossen, K.; Burgard, A. Org. Process Res. Dev. 2013,
17 (2), 282−293.
ACKNOWLEDGMENTS
■
We thank Johnson-Matthey and Takasago for their contribu-
tion on the hydrogenation of artemisinic acid, DeDietrich
(QVF), A. Peschl (UV-Consulting), and A. Braun for advice on
industrial photochemical reactor design. We also thank C.
Tanielian and D. J. MacGarvey (University of Keele, UK) for
many productive conversations and better understanding for
the photooxidation mechanism. This research was conducted
under the sponsorship of the Institute for OneWorld Health
(PATH) through generous support of the Bill & Melinda Gates
Foundation for this nonprofit project. In addition we thank
particularly D. Pellungrini, S. Morinelli, D. Curetti, S. Michelis,
M. Grasso, M. Cucini, M.P. Feth, U. Seitz-Felix, F. Fischer, C.
Keleschovsky, H. Starke, J. Heuser, M. Hochhaus, T. Schaaf, D.
(22) Feth, M. P., Rossen, K., Burgard, A. (Sanofi). EP2660234, 2013.
(23) Kraft, V., Kretzschmar, G., Rossen, K. (Sanofi). WO/2011/
030223, 2011.
(24) Alsters, P. L.; Jary, W.; Nardello-Rataj, V.; Aubry, J.-M. Org.
Process Res. Dev. 2010, 14, 259−262.
(25) Ravelli, D.; Protti, S.; Neri, P.; Fagnonia, M.; Albini, A. Green
Chem. 2011, 13, 1876.
(26) Acceptance of non-plant-derived-artemisinin by WHO,
Prequalification of Medicines Programme (PQP): http://apps.who.
int/prequal/info_press/documents/PQ_non-plant_derived_
artemisinin_1.pdf.
Horstermann, G. Kuschel, A. Augustin, O. Lenz, A. Charaf, C.
̈
Zorn, P. Sakhaii, M. Guthlein, R. Feling, C. Lattemann, L.
̈
Goldenberg, and W. Laux for their dedication and support to
achieve the success to industrialize the artemisinin manufactur-
ing process in reality.
REFERENCES
■
(1) World Health Organization, World Malaria Report, WHO,
Geneva, 2012.
(2) Wallaart, T. E.; Pras, N.; Beekmann, A. C.; Quax, W. J. Planta
Med. 2000, 66 (1), 57−62.
(3) Ro, D.-K.; Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K.
L.; Ndungu, J. M.; Ho, K. A.; Eachus, R. A.; Ham, T. S.; Kirby, J.;
Chang, M. C. Y.; Withers, S. T.; Shiba, Y.; Sarpong, R.; Keasling, J. D.
Nature 2006, 440 (7086), 940−943.
(4) Acton, N.; Roth, R. J. J. Nat. Prod. 1989, 52 (5), 1183−1185.
Acton, N.; Roth, R. J. J. Org. Chem. 1992, 57 (13), 3610−3614.
(5) Sy, L.-K.; Brown, G. D. Tetrahedron 2002, 58 (5), 897−908.
(6) Paddon, C. J.; Westfall, P. J.; Pitera, D. J.; Benjamin, K.; Fisher,
K.; McPhee, D.; Leavell, M. D.; Tai, A.; Main, A.; Eng, D.; Polichuk, D.
R.; Teoh, K. H.; Reed, D. W.; Treynor, T.; Lenihan, J.; Fleck, M.;
Bajad, S.; Dang, G.; Dengrove, D.; Diola, D.; Dorin, G.; Ellens, K. W.;
Fickes, S.; Galazzo, J.; Gaucher, S. P.; Geistlinger, T.; Henry, R.; Hepp,
M.; Horning, T.; Iqbal, T.; Jiang, H.; Kizer, L.; Lieu, B.; Melis, D.;
Moss, N.; Regentin, R.; Secrest, S.; Tsuruta, H.; Vazquez, R.;
Westblade, L. F.; Xu, L.; Yu, M.; Zhang, Y.; Zhao, L.; Lievense, J.;
Covello, P. S.; Keasling, J. D.; Reiling, K. K.; Renninger, N. S.;
Newman, J. D. Nature 2013, 496 (7446), 528−532.
(7) Schmid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105, 624−625.
(8) Zhou, W.-S. Pure Appl. Chem. 1986, 58 (5), 817−824.
(9) Avery, M. A.; Chong, W. K. M.; Jennings-White, C. J. Am. Chem.
Soc. 1992, 114, 914−919.
(10) Constantino, M. G.; Beltrame, M., Jr.; Jose da Silva, G. V. Synth.
Com. 1996, 26 (2), 321−329.
(11) Yadav, J. S.; Thirupathaiah, B.; Srihari, P. Tetrahedron 2010, 66,
2005−2009.
(12) Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2012, 134, 13577−13579.
(13) Dhainaut, J., Dlubala, A., Guevel, R., Medard, A., Oddon, G.,
Raymond, N., Turconi, J. (Sanofi). WO/2011/026865, 2011.
(14) Dhainaut, J., Dlubala, A., Guevel, R., Medard, A., Oddon, G.,
Raymond, N., Turconi, J. (Sanofi). EP2289897, 2011.
(15) Levesque, F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51
(7), 1706−1709.
(16) Kopetzki, D.; Levesque, F.; Seeberger, P. H. Chem.Eur. J.
2013, 19.
(17) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78 (13),
6384−6389.
(18) Seeberger, P. H., Kopetzki, D., Levesque, F. WO/2013/030247,
2013.
(19) Seeberger, P. H., Levesque, F., Kopetzki, D. EP2565197, 2013.
(20) Hydrogenation catalyst screening by Takasago for Sanofi,
unpublished results.
422
dx.doi.org/10.1021/op4003196 | Org. Process Res. Dev. 2014, 18, 417−422