Efficient synthesis of carbon-11 labelled acylsulfonamides using [11C]CO carbonylation chemistry

Article abstract of DOI:10.1039/c8cc09661a

Herein, a novel method for carbon-11 labeling of acyl sulfonamides by a one-step insertive [¹¹C]CO carbonylative cross-coupling reaction between aryl halides and sulfonamides is presented. Various model compounds as well as drug molecules LY573636 (tasisulam) and ABT-199 were obtained in excellent yields. This method provides a valuable and widely applicable contribution to the continuously expanding radiochemical toolbox for PET research.

Full text of DOI:10.1039/c8cc09661a

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Efficient synthesis of carbon-11 labelled
acylsulfonamides using [11C]CO carbonylation
Cite this:DOI: 10.1039/c8cc09661a
chemistry†
Received 5th December 2018,
Accepted 18th February 2019
Berend van der Wildt,
Bin Shen and Frederick T. Chin
*
DOI: 10.1039/c8cc09661a
rsc.li/chemcomm
Herein, a novel method for carbon-11 labeling of acyl sulfonamides by a transition metal-mediated cross-coupling reactions for the synthesis
one-step insertive [11C]CO carbonylative cross-coupling reaction of carbon-11 labelled amides, esters, carboxylic acids, aldehydes,
between aryl halides and sulfonamides is presented. Various model ketones, carbamates and ureas, among others.11,12 More recently,
compounds as well as drug molecules LY573636 (tasisulam) and various techniques that allow carbon-11 carbonylations to be
ABT-199 were obtained in excellent yields. This method provides a executed at atmospheric pressure have emerged.13–15 The resulting
valuable and widely applicable contribution to the continuously decreased demand for highly specialized and expensive high-
expanding radiochemical toolbox for PET research.
pressure synthesis equipment has made [11C]CO chemistry acces-
sible to more PET centres worldwide.16,17 However, to the best of
Positron emission tomography (PET), an imaging technique that our knowledge, [11C]CO carbonylation chemistry has not been
allows for quantitative visualization of biological processes at a applied for the synthesis of acylsulfonamides. As a well-known
molecular level in vivo at high spatial and temporal resolution, is carboxylic acid isostere,18 acylsulfonamides present a common
widely used in clinical diagnosis, biomedical research and drug motif in organic and medicinal chemistry and have been applied
development.1–3 PET depends on the production of radiophar- in development of inhibitors of hepatitis C virus NS3/4A protease
maceuticals, which are generally biologically active molecules inhibitors, inhibitors of the sodium channel blocker NaV1.7 used in
(e.g., ligands, inhibitors, substrates) labelled with PET isotopes pain management, angiotensin II inhibitors, antiproliferative agent
such as carbon-11 (t1/2 = 20.3 minutes) and fluorine-18 (t1/2
=
LY573636, hereafter referred to as tasisulam, anti-apoptotic Bcl-2
109.8 minutes).4 Carbon-11 is an especially attractive radioisotope proteins inhibitors amongst others.19–21 To the best of our knowl-
for radiolabelling small molecules, since carbon is widely present in edge, only one example of a carbon-11 labelled acyl sulfonamide
drug-like compounds. The shorter half-life, compared to fluorine-18, exists (Fig. 1).22 This carbon-11 labelled angiotensin II inhibitor was
also offers a lower patient radiation burden which then allows the synthesized in a three step procedure including preparation and
possibility for multiple PET studies to occur within the same day for purification of carbon-11 benzoyl chloride and subsequent reaction
a single subject. On the contrary, the short half-life of carbon-11
also presents a challenge for the radiochemist to complete the
radiochemistry and use the radiolabelled compounds within a
shorter timeframe.5,6 Continuous improvement and expansion of
the radiochemical toolbox are essential to empower the radio-
chemist to make more compounds available for radiolabelling.
A common and versatile radioactive synthon in carbon-11
chemistry is [11C]CO, typically obtained in high yields via online
heterogeneous catalytic reduction of cyclotron-produced [11C]CO2
over heated zinc or molybdenum, although other methods are
available as well.7–10 [11C]CO has been historically used in insertive
Fig. 1 Synthesis of carbon-11 labelled sulfonamides via (A) multistep
synthesis via a Grignard reagent to obtain the carbon-11 carboxylic acid,
conversion to acyl chloride and subsequent condensation reaction
towards acyl sulfonamide22 and (B) direct synthesis of carbon-11 acyl
sulfonamides via insertive transition metal mediated carbonylation reac-
tion (this work). The position of the carbon-11 label is depicted with *.
Stanford University, School of Medicine, Department of Radiology, Molecular
Imaging Program at Stanford (MIPS), 1201 Welch Road, PS049, Stanford,
CA, 4305-5484, USA. E-mail: chinf@stanford.edu
† Electronic supplementary information (ESI) available: Synthesis and character-
isation of (labelled) compounds and experimental details. See DOI: 10.1039/
c8cc09661a
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with a sulfonamide precursor molecule.22 Although impressive by
For efficiently conducting the radiochemical reactions described
itself and successful for this specific compound, such a challenging herein, a recently reported [11C]CO dispensing system was
radiosynthetic strategy results in unreliable production runs and used25 which resulted in a 10-fold increase in efficiency com-
thus hampers efforts towards clinical translation. In fact, analogues pared to traditional methods. Radiochemical reaction condi-
of the compound have been developed since that allow for more tions were derived from conditions used for synthesis of
straightforward one-step methylation procedure using [11C]CH3I.23 unlabelled acylsulfonamide,24 with modifications suitable for
The synthesis of isotopically non-enriched sulfonamides using carbon-11 chemistry. In contrast to the 15 minute reaction time
Mo(CO)6 as a solid carbon source in combination with microwave for unlabelled chemistry reactions, a five minute reaction time
heating has previously been reported.24
was chosen to minimize product loss due to the rapid decay of
The aim of the current study was to develop an efficient, carbon-11 (t1/2 20.3 minutes). Reactant and reagent amounts
reliable and broadly applicable method for the radiosynthesis of were drastically reduced (for sulfonamides and aryl halides
carbon-11 labelled sulfonamides to provide a valuable contribu- 20 mmol vs. 0.40 mmol), to allow for rapid one-step purification
tion to the radiochemical toolbox. Keeping the limitations of of products by means of semi-preparative HPLC. In addition,
carbon-11 chemistry in mind, the envisioned method is focusing THF was selected as a solvent, as this is the generally preferred
on a short reaction time (5 min), low reagent concentrations solvent in carbon-11 carbonylation reactions.13,14 Finally,
compatible with semi-preparative HPLC purification of crude microwave heating was substituted for conventional heating
reaction mixtures, and broad applicability by using conventional to increase the applicability to PET centres where microwave
radiochemistry equipment towards efficient synthesis of carbon- systems are not available within the radiochemical facility.
11 labelled acylsulfonamides.
Initially, the feasibility of [11C]CO carbonylation chemistry
Initially, a small series of acyl sulfonamides was prepared towards synthesizing acylsulfonamides was explored by preparing
according to a previously described literature procedure, i.e., a [11C]1. Using Pd(OAc)2 as the catalyst (entry 1, Table 1), a quantitative
microwave assisted palladium catalyzed carbonylation reaction [11C]CO trapping efficiency was observed, corresponding well
between aryl halides and sulfonamides with Mo(CO)6 as source of with a previous report using xantphos as the supporting
carbon monoxide (Fig. 2).24 All compounds were obtained in good ligand.14 Importantly, the radiochemical purity after reaction
yields, with the exception of 4-nitro-N-tosylbenzamide 9 (no product was 80%, demonstrating for the first time the synthesis of
formed). Compound 9, however, was eventually obtained in acylsulfonamides by [11C]CO carbonylation chemistry. A rapid
acceptable yield by reacting nitrobenzoyl chloride with toluene- screen using several commonly used catalysts showed that
sulfonamide. The obtained acylsulfonamides were characterized Pd(PPh3)2Cl2 was the optimal catalyst for this particular reaction
by 1H, 13C-NMR, and mass spectrometry and used as HPLC (entry 3), resulting in [11C]1 in 97% radiochemical yield. Use of
reference standards for subsequent radiochemical reactions.
Herrmann’s palladacycle22 resulted in the lowest trapping effi-
ciencies (71%), whereas Pd2dba3 gave the lowest radiochemical
purity (56%).
Continuing with Pd(PPh3)2Cl2 as the optimized catalyst,
various solvents ranging from non-polar solvents such as xylene
and dichloromethane to polar solvents like acetonitrile, DMSO
and DMF were screened (entries 7–15) and generally resulted in
high radiochemical yields of [11C]1 between 57–95%. Surprisingly,
despite the moderate solubility of the reagents in toluene and xylene,
these solvents provided both high trapping efficiencies as well as
high radiochemical purities. The polar solvent DMSO and DMF
resulted in low yields (57%), whereas MeCN, also a polar solvent,
resulted in considerably higher yield (90%). Overall, no correlation
between trapping efficiency, radiochemical purity or radiochemical
yield and solvent polarity was found. The high radiochemical purity
using chlorobenzene as solvent (80%) demonstrated the negligible
reactivity of aryl chlorides vs. aryl iodides. The highest radiochemical
yield in this solvent screen for this particular reaction were found
using THF (97.0 Æ 2.8, entry 3).
Next, a series of both aryl halides and sulfonamides were
subjected to the optimized reaction conditions (entry 3 in Table 1).
First, the aryl halide was varied (Table 2, entries 1–10). All com-
pounds were prepared in high radiochemical yields (62–99%). Both
electron donating as well as electron withdrawing groups were
tolerated as substituents on the aryl halide. By using both iodo- and
bromobenzene (entries 1 and 2) towards [11C]2, a higher reactivity
of iodobenzene was demonstrated. The high yielding reaction
Fig. 2 Overview of model acyl sulfonamides prepared in this work (see
ESI† for experimental conditions).
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Table 1 Screening of various palladium sources and solvents for the formation of [11C]1
Entry
Pd-Source
Solvent
TE (%)
RCP (%)
RCY (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd2dba3
PdCl2(PPh3)2
Palladacycle
Pd(PPh3)4
[(Cinnamyl)PdCl]2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
THF
THF
THF
THF
THF
THF
Xylene
Toluene
Chlorobenzene
DCM
Dioxane
EtOAc
DMF
99.9 Æ 0
99.5 Æ 1
99.9 Æ 0
71.2 Æ 2
99.9 Æ 0
99.3 Æ 1
98.0 Æ 3
99.9 Æ 0
91.5 Æ 4
75.1 Æ 16
64.1 Æ 23
95.9 Æ 3
84.0 Æ 8
85.6 Æ 1
96.5 Æ 3
80.4 Æ 3
56.3 Æ 2
97.0 Æ 3
64.7 Æ 11
93.0 Æ 2
96.9 Æ 0
94.0 Æ 1
94.7 Æ 2
79.8 Æ 2
77.0 Æ 11
86.0 Æ 7
99.0 Æ 0
68.2 Æ 2
74.7 Æ 7
92.7 Æ 1
80.4 Æ 3
56.0 Æ 1
97.0 Æ 3
45.9 Æ 7
92.9 Æ 2
96.2 Æ 1
92.1 Æ 1
94.6 Æ 2
71.8 Æ 5
57.6 Æ 13
56.9 Æ 23
94.9 Æ 3
57.3 Æ 6
64.1 Æ 6
89.5 Æ 4
9
10
11
12
13
14
15
DMSO
MeCN
TE: trapping efficiency; RCP: radiochemical purity; RCY: radiochemical yield. Results are expressed as average Æ standard deviation (n = 3). The
position of the carbon-11 label is depicted with *.
using 1-bromo-4-iodobenzene (entry 6) confirmed a preference for reactions mixtures showed minimal side product formation. Addi-
oxidative addition at iodo-position over the bromo-position, corres- tionally, excess of unreacted precursors and reagents eluted either
ponding to the more reactive iodo-functionality. The same effect for earlier (sulfonamides) or later (aryl halides) than the desired
aryl bromides over aryl chlorides was demonstrated using 1-bromo- radiolabelled products. Together, this will facilitate future product
4-chlorobenzene (entry 5). Interestingly, nitro-N-tosylbenzamide purification by decreasing the risk of collecting (radio)chemical
was synthesized in good yield (62%), despite the fact that this contaminations in the final product formulation. Following the
compound was previously not obtained in this study as a reference optimal reaction conditions, [11C]1 was synthesized and isolated in
standard using non-radioactive carbonylation chemistry.24 Various 66.8 Æ 5.3% decay corrected yield (n = 3, calculated from the
sulfonamides with either electron donating or electron with- amount of [11C]CO produced, decay-corrected to end-of-synthesis,
drawing groups showed good reactivity (entries 13–17). Besides non-decay corrected: 33.8 Æ 2.7%) in an overall synthesis time of
the generally high yields, radioHPLC chromatograms of the crude 30.6 Æ 2 minutes from end of bombardment (n = 3, see ESI† for
Table 2 Synthesis of various model acyl sulfonamides using [11C]CO carbonylation chemistry
Entry
Product
Aryl halide
TE (%)
RCP (%)
RCY (%)
1
2
3
4
5
6
7
8
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
11C]2
Iodobenzene
Bromobenzene
98.6 Æ 1
70.8 Æ 11
99.9 Æ 0
82.1 Æ 4
85.1 Æ 7
90.1 Æ 3
80.7 Æ 14
83.6 Æ 6
72.2 Æ 1
90.0 Æ 5
97.1 Æ 2
99.6 Æ 0
98.2 Æ 1
97.7 Æ 2
98.6 Æ 1
72.7 Æ 8
96.5 Æ 3
97.6 Æ 3
89.5 Æ 4
98.3 Æ 1
99.8 Æ 0
95.1 Æ 0
99.9 Æ 0
98.3 Æ 1
98.5 Æ 1
86.5 Æ 1
93.7 Æ 3
81.3 Æ 1
99.0 Æ 0
93.1 Æ 1
75.8 Æ 6
92.7 Æ 4
73.6 Æ 21
99.5 Æ 1
96.2 Æ 3
63.4 Æ 11
98.2 Æ 1
81.3 Æ 4
81.0 Æ 6
90.0 Æ 3
79.4 Æ 14
82.3 Æ 7
62.4 Æ 1
84.2 Æ 4
79.0 Æ 1
98.6 Æ 0
91.5 Æ 2
74.1 Æ 8
91.4 Æ 4
57.0 Æ 17
96.0 Æ 2
11C]2
11C]3
1-Iodo-4-methoxybenzene
1-Iodonaphthalene
1-Bromo-4-chlorobenzene
1-Bromo-4-iodobenzene
4-Iodobenzonitrile
1-Iodo-4-(trifluoromethyl)benzene
4-Iodonitrobenzene
Ethyl 4-iodobenzoate
tert-Butyl(4-iodophenyl)carbamate
3-Iodothiophene
4-Iodo-toluene
4-Iodo-toluene
4-Iodo-toluene
Bromobenzene
11C]4
11C]5
11C]6
11C]7
11C]8
9
11C]9
10
11
12
13
14
15
16
17
11C]10
11C]11
11C]12
11C]13
11C]14
11C]15
11C]16
11C]16
Iodobenzene
The position of the carbon-11 label is depicted with *.
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applications. Preclinical studies are currently underway and
will be reported in due time.
This work was achieved with financial support from the NIH
(R21 CA205564) and the Ben & Catherine Ivy Foundation.
Conflicts of interest
The authors have no conflict of interest to declare.
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Overall, an efficient, reliable and broadly applicable method
for the radiosynthesis of carbon-11 labelled acylsulfonamides
by means of palladium mediated [11C]CO carbonylation was
developed. The wide substrate scope and broad applicability
have been exemplified by the successful synthesis of both
[11C]tasisulam and [11C]ABT-199. Despite the fact that no
further reaction optimization towards these two specific drug
molecules were performed, current radiochemical yields are
sufficient for evaluating these compounds in appropriate
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¨
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