Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals

Article abstract of DOI:10.1002/ange.202008519

Radiolabelling is fundamental in drug discovery and development as it is mandatory for preclinical ADME studies and late-stage human clinical trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the commercially available and air-stable iridium precatalyst [Ir(COD)(OMe)]₂ is described. A large scope of pharmaceutically relevant substructures can be labelled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxa-/thia-zoles, thiophene, but also electron-rich phenyl groups. The high functional group tolerance of the reaction is highlighted by the labelling of a wide range of complex pharmaceuticals, containing notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.

Full text of DOI:10.1002/ange.202008519

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Zitierweise:
Internationale Ausgabe: doi.org/10.1002/anie.202008519
Deutsche Ausgabe: doi.org/10.1002/ange.202008519
Isotope Labelling
Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals
Marion Daniel-Bertrand, Sꢀbastien Garcia-Argote, Alberto Palazzolo, Irene Mustieles Marin,
Pier-Francesco Fazzini, Simon Tricard, Bruno Chaudret, Volker Derdau, Sophie Feuillastre und
Grꢀgory Pieters*
Abstract: Radiolabelling is fundamental in drug discovery and
development as it is mandatory for preclinical ADME studies
and late-stage human clinical trials. Herein, a general, effective,
and easy to implement method for the multiple site incor-
poration of deuterium and tritium atoms using the commer-
cially available and air-stable iridium precatalyst [Ir(COD)-
stage functionalization at non-labile positions, reducing thus
costs and time spent for the synthesis of the labelled com-
[
9]
pounds. Transition metal catalysis for CÀH activation has
recently known tremendous developments, allowing new HIE
reactions to emerge. Among them, one of the most used ca-
talyst for the labelling of pharmaceuticals is the Crabtreeꢀs
iridium one, which gave tritium atoms incorporation mainly at
the ortho position of a directing group under mild reaction
(
OMe)] is described. A large scope of pharmaceutically rele-
2
vant substructures can be labelled using this method including
pyridine, pyrazine, indole, carbazole, aniline, oxa-/thia-zoles,
thiophene, but also electron-rich phenyl groups. The high
functional group tolerance of the reaction is highlighted by the
labelling of a wide range of complex pharmaceuticals, contai-
ning notably halogen or sulfur atoms and nitrile groups. The
multiple site hydrogen isotope incorporation has been ex-
plained by the in situ formation of complementary catalytically
active species: monometallic iridium complexes and iridium
nanoparticles.
[
10]
conditions (see Figure 1a). Over the past 30 years, many
I
efforts have been made to improve Ir catalysts, and the work
from the group of Kerr among others have allowed to in-
[
11–18]
crease substrates compatibility.
Hoover and co-workers,
II
have also demonstrated recently that Pd species can mediate
the CÀH tritiation of pharmaceuticals with selectivities and
functional groups tolerance similar to those observed with
[19]
homogeneous Iridium catalysis. Nevertheless, such type of
catalysis still requires the presence of a suitable directing
group and particular substitution patterns to permit the for-
mation of [5] or [6]-irida- or pallada-cycle key intermediates.
Introduction
Tritium is considered as a radioactive tracer element of
[
1–3]
choice in biological studies.
In drug discovery and deve-
lopment, tritiated drug candidates are notably used: 1) to
[
4]
characterize receptors using radioligand binding assays; 2)
to provide qualitative and quantitative information on drug
distribution and pharmacokinetics; 3) to elucidate drugs
metabolic profile. For some of these important applications,
the synthesis of complex tritiated molecules with a high molar
À1
[5–7]
activity (beyond 50 Cimmol ) is mandatory.
incorporate tritium atoms into a desired molecule are nu-
Methods to
[
8]
merous, but among them Hydrogen Isotope Exchange
HIE) is clearly the most appealing one as it allows a late-
(
[*] Dr. M. Daniel-Bertrand, S. Garcia-Argote, Dr. A. Palazzolo,
Dr. S. Feuillastre, Dr. G. Pieters
Universitꢀ Paris-Saclay, CEA, INRAE, Dꢀpartement Mꢀdicaments et
Technologies pour la Santꢀ (DMTS), SCBM
Bat 547, 91191 Gif-sur-Yvette (France)
E-Mail: gregory.pieters@cea.fr
Dr. I. Mustieles Marin, Dr. P.-F. Fazzini, Dr. S. Tricard, Dr. B. Chaudret
LPCNO, Universitꢀ de Toulouse, UMR 5215 INSA-CNRS-UPS, In-
stitut National des Sciences Appliquꢀes
135, Avenue de Rangueil, 31077 Toulouse (France)
Dr. V. Derdau
Sanofi-Aventis (Deutschland) GmbH, R&D, Integrated Drug Disco-
very
Industriepark Hoechst, 65926 Frankfurt am Main (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202008519.
Figure 1. State-of-the-art of tritium labelling of drugs with T gas.
2
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Recently, to overcome these limitations, Chirikꢀs group has
developed a HIE reaction catalyzed by an iron complex al-
lowing efficient incorporation of tritium atoms mainly at the
[
20]
less sterically hindered position (Figure 1b).
Lately, the same group has also developed nickel com-
plexes to catalyze HIE reactions allowing the synthesis of
high molar activity tritiated pharmaceuticals with isotopes
incorporation in more conventional positions via the coordi-
nation of a directing atom in most cases (Figure 1c). Although
this method is certainly useful for the synthesis of tritiated
molecules, it suffers from drawbacks such as the need to
synthetize the catalyst and the apparent low functional group
[
21,22]
tolerance (fluorine, chlorine, esters and sulfones only).
Figure 2. Deuteration of 2-phenylpyridine 1 using [Ir(COD)(OMe)]2
compared to other iridium catalysts.
MacMillanꢀs group achieved another major advance in this
active field of research, by demonstrating the usefulness of
a photoredox catalyst (4Cz-IPN) for tritium labelling of ter-
tiary amines. Even if a wide range of drugs might be la-
belled using this reaction, the reported scope is still restricted
to alkylamine substructures. Moreover, the method suffers
[
23]
and confirmed by mass spectrometry). Interestingly, D-la-
belling occurred mainly in both ortho-positions of the phenyl
group and on three other positions of the pyridine moiety
(Figure 2), via directed and undirected CÀH activation pro-
from the use of in situ generated tritiated water (T O) as the
2
isotopic source, which limits its implementation in numerous
laboratories. Therefore, efficient and easy to implement HIE
methods using mild conditions, reasonable amounts of tritium
gas as the isotopic source still need to be developed to faci-
litate the access to complex labelled compounds owning high
molar activities. In this context, we report a general method
for the multiple site hydrogen isotope labelling of complex
molecules using the commercially available and air-stable
cesses, making this method useful to incorporate high levels of
hydrogen isotopes into a given molecule. To have a better
understanding on this multiple site incorporation and to start
deciphering the catalytically active species involved in this
transformation, we performed an experiment using the same
reaction conditions using IrNp/ICy as catalyst (Figure 2). In-
terestingly, in this case the main labelled positions are posi-
tions 2, 3 and 4 of the pyridine ring whereas only low deute-
rium incorporation occurred in position 5 (ca. [17]) and in
ortho and meta of the phenyl group (isotopic enrichment of
ca. [25] and [13]). Based on the fact that the use of Ir homo-
geneous catalyst lead classically to deuterium incorporation
iridium precatalyst [Ir(COD)(OMe)] . This new synthetic
2
method possesses multiple key features far beyond state-of-
the-art methods for tritium labelling including a very broad
substrate scope and an exceptional functional group tolerance
[
25]
(
see Figure 1d). Moreover, the multiple site isotope incor-
in the ortho-position of the phenyl group (1b), we started
envisioning the possible in situ generation of both Ir nano-
particles and active homogeneous complexes from [Ir-
(COD)(OMe)] under a D atmosphere. To evaluate this as-
poration explained by the in situ formation of a catalytically
active system including both monometallic Ir complexes and
Ir nanoclusters, allow the one-step synthesis of complex
pharmaceuticals owning high tritium contents (molar activi-
2
2
sumption, we undertook a detailed characterization of the
reaction mixture obtained after the deuteration process.
Transmission Electron Microscopy (TEM) was performed on
the crude reaction medium with 2-phenylpyridine 1, eviden-
cing the formation of ca. 2 nm nanoparticles with a remarka-
bly low size distribution given the absence of added stabilizers
(SI Figure S167). High-Resolution STEM (HR-STEM) sho-
wed some heterogeneity in the particle size and some coa-
lescence but, most importantly, evidenced the presence of
small clusters along with isolated iridium atoms, which could
correspond to homogeneous iridium complexes (Figure 3). It
is clear that both single atoms and nanoparticles co-exist in
the sample and it is not an artefact resulting from the electron
beam, since such isolated atoms are not observed on TEM
À1
ties up to 122 Cimmol ).
Results and Discussion
For the purpose of developing a new catalytic system for
HIE reactions of anilines, we have recently reported the
synthesis of Ir nanoparticles stabilized by ICy-NHC (1,3-di-
cyclohexylimidazol-2-ylidene) ligands (IrNp/ICy), obtained
by decomposition of the [Ir(COD)(OMe)] complex under an
2
[
24]
H atmosphere. During the course of this study, we have
2
discovered the powerful reactivity of this commercially
available and air-stable complex itself, as a precatalyst to
perform HIE reactions on various substructures without ad-
ding any additional ligand. Interesting preliminary results
were obtained for the deuteration of 2-phenylpyridine
[
26]
grids of IrNp/ICy. Mass analysis confirmed the presence in
the reaction mixture of iridium complexes accommodating
two 2-phenylpyridine ligands (SI Figure S171 and Fig-
ure S172).
1
(Figure 2).
The HIE reaction was conducted under D gas as the
To the best of our knowledge the combination of both
homogeneous and heterogeneous catalysts in HIE reactions
to obtain improved deuterium atoms incorporation was only
explored by Schou, with the mixing of Crabtreeꢀs homogen-
2
isotopic source (1 bar) in THF at 558C (Figure S2 and Tab-
le S1 for optimization studies). A high deuterium incorpora-
tion was obtained for 1 with a total incorporation of 4.4
1
[27]
deuterium atoms (determination based on H NMR analysis
eous iridium catalyst and rhodium black. The results de-
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nylthiophene 16. Pleasantly, by increasing the catalyst loading
up to 7.5 mol%, the desired labelled molecule was obtained
with up to 0.9 deuterium atoms. Then, we demonstrated that
this easy-to-implement method can be used to deuterate
a broad variety of complex pharmaceuticals (Figure 5).
Carvedilol 17 and Carprofen 18, two carbazole der-
ivatives, were successfully deuterated highlighting notably the
functional group tolerance of the method towards free alco-
hols, chlorine atoms and carboxylic acids (Figure 5A). Azines
and indoles, common scaffolds in small drugs approved by
[
29]
FDA and therefore substructures of interest in the context
of HIE methods development, were labelled including indole
derivatives such as melatonine 19, zafirlukast 20, indole-3-
lactic acid 21, yohimbine 22, tadalafil 23 and vilazodone 24
(Figure 5B). These results show the tolerability of the method
towards nitrile moieties usually prone to be reduced or to
inactivate the catalyst due to strong binding, but also towards
recurrent functional groups in pharmaceuticals such as esters,
primary and tertiary amides, carbamates, methoxy groups and
sulfonamides. Pharmaceutical compounds containing a pyri-
dine moiety were also used as substrates and nicotine 25,
brompheniramine 26, doxylamine 27 and bisacodyl 28 (up to
4.5 deuterium atoms incorporated) gave attractive results in
terms of deuterium uptakes, regioselectivities of labelling and
functional group tolerance (bromide, alkyl amines, phenol
esters). Regarding aniline derivatives, important moieties in
pharmaceuticals, few methods exist nowadays for their la-
Figure 3. Bright field STEM (left) and HAADF STEM (right) images of
iridium nanoparticles. They are formed in situ with 2-phenylpyridine
evidencing the presence of both nanoparticles and dispersed atoms
(
shown by the arrows).
scribed were very dependent on the substrates used, and the
benefit of using the mixture of catalysts was not significant in
most cases.
In order to study the reaction scope related to the use of
[
Ir(COD)(OMe)] as precatalyst for HIE, we have performed
2
reactions using diverse pharmaceutically relevant hetero-
cycles as substrates (Figure 4).
Starting from phenylpyridines (1c, 2, 3), as the phenyl
group move away from the coordinating nitrogen atom, we
observed a decrease in the ortho-position labelling, but the 2-
and 6- positions were still labelled with high efficiency via
a directed CH-activation performed by an homogeneous Ir
complex (Figure 4A). Positions 3, 4 and 5 of the pyridine, as
well as the meta- and para-positions of the phenyl group were
labelled via a undirected CH-activation promoted by Ir na-
noparticles. These regioselectivities are in accordance with
our hypothesis of the formation of mixed catalytic species in
situ. The method was then applied to gain access to high
deuterium atoms incorporation on various heterocycles
[24]
belling. Here, anilines 29, 30 and 31 gave the desired deu-
terated compounds with the D atom located at the ortho-
position of the nitrogen atom (Figure 5C) with a higher
deuterium incorporation compared to the one obtained using
IrNp/ICy in THF. Lenalidomide 31 was also deuterated on the
para-position of the aromatic moiety and diclofenac me-
thylester 32, a secondary aniline, was labelled with 0.5 deu-
terium atoms. Complex structures were also studied like
imipramine 33, where the labelling occurred mainly on the
aromatic ring (Figure 5D) orthogonal to the previously de-
(
Figure 4B) thanks to the multiple site labelling, with a re-
[
30]
quired minimum of 1.6 deuterium atoms incorporated (cor-
scribed positions using Ru nanoparticles or the MacMil-
lanꢀs photoredox reaction, where the aliphatic positions were
À1
responding to a molar activity of 50 Cimmol if the isotope
[23]
incorporated is tritium). Indeed, the reaction worked well
with 3-picoline 4 or simple pyridine 5 with a deuterium in-
corporation in positions 2 and 6 probably due to the coordi-
nation of the nitrogen atom at the surface of the in situ gen-
erated Ir clusters, but also on the more challenging positions
labelled. Another complex molecule, paroxetin 34, gave the
deuterated product with 1.2 D overall enrichment, with iso-
tope incorporation on the electron-rich aromatic group des-
pite the presence of the strongly coordinating secondary al-
kylamine unit. Finally, Retro 2.1, a molecule of therapeutic
interest in the context of cells protection against Shiga to-
3
, 4 and 5 via undirected CÀH activation. Indole 6 and 1-
[
31]
methylindole 7 were labelled on up to three positions and for
pyrazine 8 all the positions are labelled with a total incor-
poration of 2.6 deuterium atoms. Labelling of imidazole 9,
pyrazole 10 and triazole 11 gave high deuterium incorpora-
tion both on the heterocycle core and on the aromatic ring
showing the potency of the method. Oxazole 12, aniline 13
and carbazole 14 were other compatible moieties for this
reaction extending further the scope of application. Caffeine
xins, was labelled nicely, albeit with an increase of the ca-
talytic loadings up to 0.5 equivalent (Figure 5E). The multiple
site incorporation and high functional groups tolerance have
motivated us to adapt our reaction conditions for the tritium
labelling of pharmaceuticals (Figure 6). Indeed, our method
should allow the one-step synthesis of tritiated molecules with
good to very high molar activities, which are quite challenging
to obtain with existing methods.
1
5 was also successfully deuterated broadening the scope to
The reaction conditions were identical to the deuteration
experiments except that we employed a higher amount of
nucleobases (Figure 4C). Thiophenes are known to be diffi-
cult to label by HIE in mild conditions because of the po-
tential poisoning of the catalyst due to the sulphur atom.
Nevertheless, with our optimized conditions 0.4 deuterium
atoms was incorporated on the alpha position of the 2-phe-
catalyst (0.5 equiv) and subatmospheric pressures of T gas
2
[28]
(around 800 mbar) to reduce the risk related to tritium gas
leakage in laboratories (mandatory for industry). Considering
the high added value of tritiated pharmaceuticals, the use of
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Figure 4. Ir-catalyzed deuteration of heterocycles. Reaction conditions: 2.5 mol% of [Ir(COD)(OMe)] , 0.2 mmol of the substrate in THF (0.1m) at
2
5
58C under 1 bar of D gas. A) Study on regioselectivity of the labelling on phenylpyridines. B) High deuterium atoms incorporation. C) Labelling
2
of caffeine and 2-phenylthiophene. *7.5 mol% of [Ir(COD)(OMe)] was used.
2
such amounts of air-stable and commercially available cata-
lyst is not a major concern. For compounds bearing indole or
pyridine moieties that is, imipramine, bisacodyl, brom-
of our knowledge, the highest value obtained by HIE so far.
Moreover, the presence of sensitive functions such as nitrile
groups or halogens were again not an issue for the labelling.
Complex molecules bearing substructures known to be hardly
labelled such as carbazole (carprofen, tadalafil) or sulphur
moieties (Retro 2.1), were obtained with satisfactory molar
activities, opening new horizons for the fast supply of difficult
to label drug compounds (Figure 6B).
pheniramine and vilazodone, molar activities higher than
À1
5
0 Cimmol were obtained (Figure 6A), significantly ex-
ceeding the standards required for drug development appli-
cations and fulfilling the requirement for their use as probes
for radioligand binding assays or autoradiography studies.
Amazingly, tritiated bisacodyl was obtained with an out-
À1
standing molar activity of 122 Cimmol which is, to the best
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Figure 5. Ir-catalyzed deuteration of pharmaceuticals. Reaction conditions: 2.5 mol% of [Ir(COD)(OMe)] , 0.2 mmol of the substrate in THF
2
(
0.1m) at 558C under 1 bar of D gas for 22 h. A) Deuterated carbazole pharmaceuticals. B) Deuterated azine moieties. C) Deuterated primary
2
and secondary anilines. D) Deuterated complex pharmaceuticals. E) Deuterated sulphur-containing pharmaceuticals. **50 mol% of [Ir(COD)-
OMe)] was used.
(
2
Conclusion
carbazoles, oxa- and thiazoles, thiophenes and nucleobases; 3)
a high functional group tolerance with a compatibility with
halogen (Cl, Br, F) and nitrile-containing compounds, usually
challenging to label using HIE methods; 4) a multiple site
isotope incorporation allowing the one-step synthesis of
complex pharmaceuticals with high deuterium contents or
In conclusion, we have demonstrated that [Ir(COD)-
OMe)] , a commercially available and air-stable Ir dimer, can
(
2
be used as precatalyst to generate in situ, under a D or T
2
2
atmosphere, Ir complexes and nanoclusters catalytically ac-
tive for Hydrogen Isotope Exchange. Compared to state of
the art methods for deuterium/tritium labelling, this approach
possesses multiple key features: 1) the use of an easy to
handle, air-stable and commercially available catalyst; 2)
a very broad substrate scope allowing the labelling of recur-
rent substructures in pharmaceuticals such as azines, indoles,
À1
very high molar activities (up to 122 Cimmol ); 5) the pos-
sibility to label positions known to be difficult with existing
methods. All these features, allied with the easy imple-
mentation of this method in laboratories (even for non-spe-
cialists) will facilitate the synthetic access to deuterated/tri-
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Figure 6. Ir-catalyzed tritiation of pharmaceuticals. Reaction conditions: 0.5 equiv of [Ir(COD)(OMe)] , 0.01 mmol of the substrate in THF
2
(
0.02m) at 558C, overnight. P(rt): pressure at room temperature. A) High molar activity tritiated pharmaceuticals. B) Complex tritiated pharma-
ceuticals. *0.8 equiv of [Ir(COD)(OMe)] was used.
2
tiated analogs of complex molecules, which are essential
diagnostic tools in drug discovery and development.
hydrogen isotope labelling · tritium
[
[
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GP thanks the European Unionꢀs Horizon 2020 research and
innovation program under the Marie Sklodowska-Curie grant
agreement no. 675071 for funding AP. M.D.B., S.G.A., A.P.,
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&
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www.angewandte.de
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. 2020, 132, 2 – 9
These are not the final page numbers!

Angewandte
Forschungsartikel
Chemie
Forschungsartikel
Isotope Labelling
M. Daniel-Bertrand, S. Garcia-Argote,
A. Palazzolo, I. Mustieles Marin,
P.-F. Fazzini, S. Tricard, B. Chaudret,
V. Derdau, S. Feuillastre,
A general method for the multiple site
hydrogen isotope labelling of complex
molecules using the commercially avail-
able and air-stable iridium precatalyst [Ir-
features far beyond the state-of-the-art
G. Pieters*
&&&& — &&&&
methods for tritium labelling, including
a very broad substrate scope and an
exceptional functional group tolerance
facilitating the access to complex phar-
maceuticals with high molar activities.
Multiple Site Hydrogen Isotope Labelling
of Pharmaceuticals
(COD)(OMe)] is reported. This new
2
synthetic method possesses multiple key
Angew. Chem. 2020, 132, 2 – 9
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.de
&&&&
These are not the final page numbers!