Synthesis of tritium and carbon-14 labelled NNC 61-4655: A potent dual-acting PPARα and PPARγ agonist

Article abstract of DOI:10.1002/jlcr.725

The synthesis of the potent dual-acting PPARα and PPARγ agonist NNC 61-4655 labelled with tritium and carbon-14 is reported. Tritium labelled NNC 61-4655 was obtained in three steps with introduction of tritium through catalytic tritium-halogen exchange o

Full text of DOI:10.1002/jlcr.725

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 861–871.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.725
Research Article
Synthesis of tritium and carbon-14 labelled NNC
61-4655: a potent dual-acting PPARa and PPARc
agonist
Steen K. Johansen* and Lars Martiny
Isotope Chemistry, CMC Development, Novo Nordisk A/S, Novo Nordisk Park,
(
DK-2760 Malꢀv, Denmark
Summary
The synthesis of the potent dual-acting PPARa and PPARg agonist NNC 61-
4655 labelled with tritium and carbon-14 is reported. Tritium labelled NNC 61-
4655 was obtained in three steps with introduction of tritium through catalytic
tritium-halogen exchange of an aryl bromide precursor. This provided
[3H]NNC 61-4655 in 39% overall radiochemical yield with a specific activity
of 49 Ci/mmol. Carbon-14 labelled NNC 61-4655 was obtained in five steps
starting from bromo[1-14C]acetic acid. The synthetic sequence, which included
a Horner–Wadsworth–Emmons olefination and a Mitsunobu alkylation,
provided [14C]NNC 61-4655 in 33% overall radiochemical yield with a specific
activity of 57.4 mCi/mmol. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: carbon-14; tritium; type 2 diabetes; PPARa and PPARg agonist;
HWE olefination.
Introduction
Diabetes mellitus is a metabolic disease affecting a still more significant
proportion of people worldwide.1 Type 2 diabetes is the most prevalent
type of diabetes mellitus and is characterized by insulin resistance,
(
*Correspondence to: S. K. Johansen, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malꢀv,
Denmark. E-mail: skjo@novonordisk.com
Copyright # 2003 John Wiley & Sons, Ltd.
Received 18 March 2003
Accepted 28 April 2003

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S. K. JOHANSEN AND L. MARTINY
hyperglycaemia, and often hyperlipidemia. Besides exercise and diet, a
number of drugs are available for the treatment of type 2 diabetes. One
such class is the peroxisome proliferator–activator receptor agonists,
which lowers blood glucose through an insulin sensitizing mechanism
ascribed to the activation of the PPARg receptor subtype.2 Unfortu-
nately, these drugs also give rise to weight gain in patients,3 which is
problematic, as obesity is a major concern in connection with type 2
diabetes. Activation of the related PPARa receptor subtype leads to
lowered plasma triglycerides in humans4 and has been reported to
induce weight loss in rodents.5 A drug, which improves both insulin
sensitivity and effectively decreases hyperlipidemia, would thus be
valuable in the management of type 2 diabetes.
Ragaglitazar, a potent dual-acting PPARg and PPARa agonist, has
been investigated in clinical trials for the treatment of type 2 diabetes
(Figure 1).6–8 NNC 61-4655, a structurally related compound, is
likewise a potent PPARg and PPARa agonist with an interesting
profile.9 To further investigate the possible use of NNC 61-4655 as a
drug for the treatment of type 2 diabetes, radiolabelled NNC 61-4655
was required.
The biodistribution and metabolic fate of potential drug candidates
are routinely investigated in ADME (absorption, distribution, metabo-
lism, and excretion) and WBA (whole-body autoradiography) studies.
These studies are commonly performed using tritium and carbon-14
labelled tracers. Labelling with tritium offers the advantage of high
specific activity, and generally, the label can be introduced in few
synthetic steps making tritium tracers very useful for early exploratory
investigations. The high specific activity of tritium also makes tritium
Figure 1. Structure of Ragaglitazar and NNC 61-4655
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SYNTHESIS OF TRITIUM AND CARBON-14
863
labelled tracers very useful in screening assays. However, compared to
carbon-14, tritium offers considerably less metabolic stability, and for
this reason, a carbon-14 labelled tracer is used in most ADME studies.
Normally, carbon-14 labelling requires a more lengthy synthetic route in
order to incorporate the label in a metabolically stable position.
Here, we report on the labelling of NNC 61-4655 with tritium and
carbon-14 for use in in vitro and in vivo investigations.
Results and discussion
Tritium Labelling
A direct approach to [3H]NNC 61-4655 using catalytic tritium–halogen
exchange of an appropriate bromo derivative was not considered
feasible, as the target molecule contained two unsaturated moieties
prone to reduction. Likewise, NNC 61-4655 was not viewed as suitable
substrate for the organoiridium catalysed hydrogen isotope exchange
reaction. Therefore, we decided to introduce tritium by tritium–halogen
exchange on the dibromo phenolic derivative 2. Subsequent coupling
with the allyllic chloride 4 and hydrolysis would lead to [3H]NNC 61-
4655 (6) (Scheme 1).
The bromo precursor 2 was prepared by reaction of the phenol 1 with
excess bromine in dichloromethane.y This gave introduction of two
bromines ortho to the phenolic moiety and provided 2 as an oil in
quantitative yield. Attempted purification of 2 by flash chromatography
on silica led to extensive decomposition, and furthermore, the
compound proved to be light sensitive. Therefore, it was decided to
use the crude material directly in the next step.
Catalytic dehalogenation of 2 using tritium gas and Pd/C in THF
proceeded smoothly to give 3 in high yield (82% based on 2) and good
purity. Although 3 could easily be purified at this stage, it is our
experience that the crude tritiated compounds after removal of labile
tritium can be reacted further without major problems, thereby avoiding
an often time-consuming purification step and at the same time
minimizing handling and loss of material. Impurities carried forward
in the synthetic sequence will most likely be removed in the final
purification step. Thus, crude 3 was coupled directly with the allylic
y The reaction was also performed using Br2 in ethanol. This, however, led to extensive trans-
esterfication.
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S. K. JOHANSEN AND L. MARTINY
Scheme 1. Synthesis of [3H]NNC 61-4655
chloride 4 in the presence of cesium carbonate8 to provide crude 5 in
quantitative yield. Hydrolysis of the reaction mixture followed by
purification on HPLC provided [3H]NNC 61-4655 (6) (47%) in
39% overall yield with a radiochemical purity > 98%. The specific
radioactivity was determined to 49 Ci/mmol by mass spectroscopy. A
method for the analysis of the enantiomeric purity was not developed,
as previous experiments have shown that the chiral center in the phenyl
propionic acid moiety does not racemise under the reaction conditions
employed.8,10
Carbon-14 Labelling
For the labelling of NNC 61-4655 with carbon-14, it was decided to
introduce the label near the alkene moiety, as this was viewed to be a
metabolically stable position compatible with the planned ADME
studies. The labelling could be accomplished by subjecting phenyl
propargylaldehyde to a Horner–Wadsworth–Emmons olefination
(HWE), which eventually would place the label in the allylic position.
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SYNTHESIS OF TRITIUM AND CARBON-14
865
Scheme 2. Synthesis of [14C]NNC 61-4655
Although triethyl phosphonoacetate, the desired HWE reagent, is
commercially available in its carbon-14 labelled form, it is an expensive
starting material, and therefore, we looked for a cheaper alternative.
Bromo[1-14C]acetic acid is a cheap commercially available starting
material, which can be converted into triethyl [1-14C]phosphonoacetate
in one step.11 Thus, triethyl [1-14C]phosphonoacetate (8) was prepared
from bromo[1-14C]acetic acid by esterfication with HCl in ethanol
followed by reaction with triethyl phosphite. Subsequently, the product
was employed in a stereoselective9 HWE reaction with phenyl
propargylaldehyde (7) and gave the ester 9 in 75% yield as the only
observed isomer (Scheme 2).z
Reduction of the ester functionality in 9 was accomplished with
diisobutylaluminium hydride (Dibal-H), which gave the allylic alcohol
z We did encounter some problems in reproducing this reaction. In our opinion, most likely this is
due to the Arbuzov reaction between ethyl bromo[1-14C]acetate and triethyl phosphite being very
sluggish. Currently, this is being investigated in our laboratories.
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S. K. JOHANSEN AND L. MARTINY
10 in good yield (68%). Conversion to the allylic chloride would then set
the stage for coupling with the phenol 1. However, this would introduce
an additional step compared to a direct Mitsunobu coupling between 10
and 1, and we decided to pursue the latter strategy. Thus, reaction of 10
and 1 with tributyl phosphine and 1,10-(azodicarbonyl)dipiperidine
(ADDP) proceeded to give the ester 11 in good yield (77%) after flash
chromatography. The use of the Mitsunobu reaction was also
investigated for the preparation of the tritium labelled compound 5.
However, the small scale employed when working with tritium makes
anhydrous chemistry difficult, and in our hands, the Mitsunobu
coupling between 3 and the corresponding alcohol failed to react most
likely due to the difficulty of keeping the reaction sufficiently dry.
Hydrolysis of 11 with aqueous sodium hydroxide furnished
[14C]NNC 61-4655 (12) (85%) in 33% overall yield with a radiochemical
purity >98% after purification by HPLC. The specific radioactivity was
determined to 57.4 mCi/mmol by mass spectroscopy.
Conclusion
In summary, we have developed synthetic routes for the labelling of the
dual acting PPARa and PPARg agonist NNC 61-4655 with tritium and
carbon-14. NNC 61-4655 was labelled with tritium in the phenyl
propionic acid moiety in 39% overall yield with tritium introduced by a
tritium–halogen exchange reaction performed on the aryl bromide
precursor 2. Likewise, NNC 61-4655 was labelled with carbon-14 in the
allylic position in 33% overall yield starting from bromo[1-14C]acetic
acid. Following HPLC purification, the products were obtained in high
radiochemical purity (>98% in both cases) and with high specific
radioactivity (49 Ci/mmol and 57.4 mCi/mmol for tritium and carbon-
14, respectively).
Experimental
General
Bromo[1-14C]acetic acid (specific activity: 58 mCi/mmol) was supplied
by Amersham Biosciences, UK. Reactions using tritium gas were
performed on a custom build tritium handling unit from RC Tritec AG,
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SYNTHESIS OF TRITIUM AND CARBON-14
867
Switzerland, who also supplied the tritium gas. Tritium gas was stored
in the form of U3H3 and was prepared in situ by heating the uranium
bed. Phenyl propargylaldehyde, isopropyl (S)-3-(4-hydroxyphenyl)-2-
ethoxypropionate, and (E)-(5-chloro-pent-3-en-1-ynyl)-benzene were
supplied by Chemical Development, Novo Nordisk A/S. All reagents
and solvents were of analytical grade and used without further
purification.
HPLC was performed using a Merck Hitachi Intelligent Pump
L6200A equipped with a Merck Hitachi Column Thermostat T6300
(operated at 408C) with a Rheodyne injector and Merck Hitachi UV
Detector L4000A (detection at 273 nm). Detection of carbon-14 and
tritium was performed on a Canbarra Packard Flow Detector A-500.
The following system was used for analytical HPLC: RP C18 column
(
(4.6 ꢀ 250 mm, 5 mm, OdDMeSi 120 A, Novo Nordisk) using a flow of
1.0 ml/min with a gradient running from 60:40 to 40:60 A/B over 40 min
followed by 0:100 A/B for 10 min (A: 10% acetonitrile in 0.1% aq.
TFA, B: 90% acetonitrile in 0.1% aq. TFA). Purifications were carried
out using the same system employing 4.6 ꢀ 250 mm and 10 ꢀ 250 mm
columns for tritium (1.0 ml/min) and carbon-14 (5.0 ml/min), respec-
tively. Radioactivity measurements were performed on a Packard Tri-
Carb 1000 liquid scintillation analyzer using Ultima FloTM M (Packard
Bioscience) as liquid scintillation cocktail. Specific activities were
determined on a Sciex API 300 mass spectrometer equipped with an
1
ionspray interface. H NMR spectra were recorded on a Bruker DRX
300 spectrometer. Flash chromatography was performed with silica gel
(
60 A (Merck, 230 – 400 mesh) and radio-TLC was performed on a
Bioscan Imaging Scanner System 200A using Merck F254 precoated
silica plates.
Isopropyl (S)-2-ethoxy-3-(3,5-dibromo-4-hydroxyphenyl)-propionate (2)
A solution of Br2 in dichloromethane (0.20 g/ml, 1.1 ml, 1.4 mmol) was
added to a solution of isopropyl (S)-2-ethoxy-3-(4-hydroxyphenyl)-
propionate (1) (67.4 mg, 0.27 mmol) in dichloromethane (10 ml) under
protection from light. The reaction mixture was stirred for 1.5 h at rt
and then added further Br2 in dichloromethane (0.20 g/ml, 1.1 ml,
1.4 mmol) followed by stirring for 1 h. Concentration in vacuo provided
2 directly as light sensitive orange oil (0.15 g, 100%), which was pure as
1
seen by H NMR. Further purification by flash chromatography on
1
silica gel lead to extensive decomposition of 2. H NMR (300 MHz,
CDCl3) d 1.18 (3 H, t), 1.21 (3 H, d), 1.25 (3 H, d), 2.89 (2 H, d), 3.36
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868
S. K. JOHANSEN AND L. MARTINY
(1 H, m), 3.63 (1 H, m), 3.91 (1 H, dd), 5.06 (1 H, m), 5.80 (1 H, br s),
7.36 (2 H, s).
Isopropyl (S)-2-ethoxy-3-([3,5-3H2]-4-hydroxyphenyl)-propionate (3)
Pd/C (10%, 6.5 mg) and Et3N (10 ml, 72 mmol) were added to a solution
of isopropyl (S)-2-ethoxy-3-(3,5-dibromo-4-hydroxyphenyl)-propionate
(2) (7.9 mg, 19.3 mmol) in THF (0.4 ml). The reaction mixture was
degassed by three freeze/thaw cycles and stirred overnight with tritium
gas (8.1 Ci). Excess tritium gas was reabsorbed on to an uranium waste
bed followed by filtration of the reaction mixture and lyophilisation
with ethanol (3 ꢀ 1 ml) in order to remove labile tritium. Finally, the
residue was dissolved in acetonitrile (5 ml) to give 3 (772 mCi, 49 Ci/
mmol, 82% based on 2) with a radiochemical purity of 87%.
Isopropyl (E)(S)-2-ethoxy-3-[[3,5-3H2]-4-(5-phenyl-pent-2-en-4-yny-
loxy)-phenyl]-propionate (5)
Cs2CO3 (32.2 mg, 98.8 mmol) and isopropyl (S)-2-ethoxy-3-([3,5-3H2]-4-
hydroxyphenyl)-propionate (3) (77.2 mCi, 1.58 mmol) in acetonitrile
(0.5 ml) were added to a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-
benzene (4) (8.1 mg, 45.9 mmol) in acetonitrile (1 ml). The reaction
mixture was stirred for 2 h at 608C. This provided 5 (77.2 mCi, 100%)
with a radiochemical purity of 75%. The reaction mixture was used
directly in the next step.
(E)(S)-2-Ethoxy-3-[[3,5-3H2]-4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid (6)
Aqueous NaOH (1N, 0.5 ml) was added to a solution of isopropyl
(E)(S)-2-ethoxy-3-[[3,5-3H2]-4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-pro-
pionate (5) (77.2 mCi, 1.58 mmol) in acetonitrile (1.5 ml), and the
reaction mixture was stirred for 3 h at 608C. The reaction was quenched
by addition of aqueous HCl (2N, 1.0 ml). The reaction mixture was
purified by HPLC, which provided 6 (36.6 mCi, 47%) in 39% overall
yield with a radiochemical purity >98%. The specific radioactivity was
determined to be 49 Ci/mmol (MS).
Triethyl [1-14C]phosphonoacetate (8)11
A solution of HCl in ethanol (0.5 ml-made by passing HCl (g) through
ethanol) was added to a solution of bromo[1-14C]acetic acid (26.6 mCi,
specific activity: 58 mCi/mmol) in ethanol (1 ml) and the mixture was
stirred for 7.5 h. Approximately half of this solution was transferred to a
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SYNTHESIS OF TRITIUM AND CARBON-14
869
5 ml pressure vial, added P(OEt)3 (2 ml), and the lid was tightly closed.
The mixture was stirred at 1408C for 5.5 h and stored at ꢁ208C
overnight. The mixture was transferred to a pear-shaped flask using
ethanol (2 ml) and concentrated (1 mm Hg, bath temperature 558C) to a
yellow oil (approx. 0.2 ml), which was dissolved in toluene (1 ml) and
used directly in the next step.
Ethyl [1-14C]-5-phenyl-pent-2-en-4-ynoate (9)
A solution of triethyl [1-14C]phosphonoacetate (8) (13.3 mCi,
0.23 mmol) in toluene (1 ml) was added to a slurry of sodium ethoxide
(24.9 mg, 0.42 mmol) in dry toluene (2 ml) under nitrogen resulting in a
clear solution, which was stirred for 40 min at rt. Phenyl propargy-
laldehyde (7) (40.3 mg, 0.31 mmol) in toluene (1 ml) was added, and the
resulting thick slurry was stirred for 1.5 h. The reaction mixture was
quenched with 10% aqueous H2SO4 (5 ml) followed by addition of
toluene (25 ml). The phases were separated and the aqueous phase
further extracted with toluene (25 ml). The combined organic phases
were washed with sat. NaHCO3 (5 ml), dried (MgSO4) and concentrated
to an oil, which was dissolved in ethanol (20 ml). This provided 9 (9.91
mCi, 75%) with a radiochemical purity of 88%.
(E)-[1-14C]-5-Phenyl-pent-2-en-4-yn-1-ol (10)
Diisobutylaluminium hydride (1.2 M in toluene, 0.5 ml, 0.60 mmol) was
added to a solution of ethyl [1-14C]-5-phenyl-pent-2-en-4-ynoate (9)
(4.95 mCi, 0.085 mmol) in dry toluene (5 ml) under nitrogen and stirred
for 1 h at rt. The reaction mixture was quenched with 10% aqueous
H2SO4 (5 ml) and stirred for 10 min followed by addition of
dichloromethane (25 ml). The phases were separated and the aqueous
phase further extracted with dichloromethane (25 ml). The combined
organic phases were washed with brine (5 ml), dried (MgSO4) and
concentrated to an oil, which was dissolved in ethanol (10 ml). This
provided 10 (3.39 mCi, 68%) with a radiochemical purity of >98%.
Isopropyl (E)(S)-2-ethoxy-3-[4-([1-14C]-5-phenyl-pent-2-en-4-ynyloxy)-
phenyl]-propionate (11)
A solution of isopropyl (S)-2-ethoxy-3-(4-hydroxyphenyl)-propionate
(1) (26.4 mg, 0.10 mmol) in dry THF (1.0 ml) was added to a solution of
(E)-[1-14C]-5-phenyl-pent-2-en-4-yn-1-ol (10) (2.77 mCi, 0.048 mmol) in
dry THF (3 ml) under nitrogen. The mixture was cooled to 0 8C, and
tributyl phosphine (70 ml, 0.28 mmol) was added followed by a solution
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S. K. JOHANSEN AND L. MARTINY
of 1,10-(azodicarbonyl)dipiperidine (55.8 mg, 0.22 mmol) in dry THF
(1.0 ml). The mixture was stirred for 1 h, during which a slow
precipitation was observed. The mixture was concentrated to dryness
and dissolved in dichloromethane (60 ml). The organic phase was
washed with water (2 ꢀ 15 ml) followed by re-extration of the aqueous
phases with dichloromethane (15 ml). The combined organic phases
were washed with brine (20 ml), dried (MgSO4), and concentrated.
Purification by flash chromatography (ethyl acetate/heptane 2:8) gave a
clear oil, which was dissolved in ethanol (5 ml). This provided 11 (2.14
mCi, 77%) with a radiochemical purity of >98%.
(E)(S)-2-Ethoxy-3-[4-([1-14C]-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid (12)
Aqueous NaOH (1 N, 2 ml) was added to a solution of isopropyl (E)(S)-
2-ethoxy-3-[4-([1-14C]-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionate (11)
(2.14 mCi, 0.037 mmol) in ethanol (5 ml), and the mixture was stirred at
708C for 1.5 h. The mixture was cooled to rt, and aqueous HCl (1 N,
2.5 ml) was added (pH52).
The crude reaction mixture was purified by HPLC. The combined
fractions containing product were concentrated to dryness} to give a
white solid, which was dissolved in ethanol (5 ml). This provided 12
(1.82 mCi, 85%) in 33% overall yield with a radiochemical purity of
>98%. The specific activity was determined to 57.4 mCi/mmol (MS).
Acknowledgements
We are grateful to Mrs. Lone Sꢀrensen for invaluable technical
assistance and Mr. Ole Wassmann for mass spectra analyses.
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SYNTHESIS OF TRITIUM AND CARBON-14
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