Synthesis of C-14 radiolabeled glucagon receptor antagonist and its use in a human mass balance study

Article abstract of DOI:10.1002/jlcr.3477

The synthesis of the radiolabeled glucagon receptor antagonist 1-[¹⁴C] was accomplished based on decarboxylative iodination of acid 2 followed by “reattachment” of ¹⁴C carboxylic function. The method allowed a significant reduction i

Full text of DOI:10.1002/jlcr.3477

Received: 27 August 2016
DOI 10.1002/jlcr.3477
Revised: 4 October 2016
Accepted: 26 October 2016
R E S E A R C H A R T I C L E
Synthesis of C‐14 radiolabeled glucagon receptor antagonist and
its use in a human mass balance study
Boris A. Czeskis | Darlene K. Satonin
Lilly Research Laboratories, Eli Lilly and
The synthesis of the radiolabeled glucagon receptor antagonist 1‐[14C] was accom-
Company, Indianapolis, IN, USA
plished based on decarboxylative iodination of acid 2 followed by “reattachment” of
Correspondence
Boris A. Czeskis, Lilly Research Laboratories, Eli
14C carboxylic function. The method allowed a significant reduction in the number
Lilly and Company, Indianapolis, IN 46285, USA.
of steps in preparation of the radiolabeled compound. Iodide 4, obtained by the
Email: czeskis@lilly.com
halodecarboxylation, was converted to cyanide 5‐[14C], which was hydrolyzed to
provide the radiolabeled acid 2‐[14C]. Coupling with β‐alanine fragment and hydro-
lysis of ester 6‐[14C] completed the synthesis of the target molecule 1‐[14C]. The
resulting compound was utilized in a mass balance and metabolism study where
hepatic oxidation followed by a trace amount of sulfate conjugation and elimination
was the main clearance pathway for 1 in humans.
KEYWORDS
carbon‐14, decarboxylative halogenation, glucagon receptor antagonist, metabolism,
radiolabeled, synthesis
1
|
INTRODUCTION
chloride and 4‐tert‐butylphenylboronic acid (Scheme 1).
The scheme includes 2 stages for generation of an optically
pure chiral center. One of them consists of asymmetric ketone
reduction assisted by the chiral oxaborolidine in the begin-
ning of the synthesis. The optical purity of the resulted sec-
ondary alcohol is not high enough at this point (90‐95%
ee). Therefore, the second chiral purification step is required
at a later stage of the synthesis: preparation and crystalliza-
tion of L‐cinchonidine salt of acid 2.
An alternative multistep synthesis of compound 1, based
on the copper‐catalyzed ring opening trifluoromethylation of
the substituted cyclopropanol, was recently published.4
An introduction of the radiolabel using the above
methods would be impractical. We envisioned a more effi-
cient approach based on halodecarboxylation of the optically
pure acid 2 followed by 14C cyanation and hydrolysis to
afford 14C carboxylic acid (Scheme 2).
Glucagon is a hormone produced by the pancreas and
released when the glucose level in blood is low (hypoglyce-
mia).1,3 Inhibition of glucagon function has potential for the
improvement of glucose control in the treatment of type 2
diabetes.1,3 Glucagon receptor antagonists have shown glu-
cose‐lowering efficacy in both acute studies1 and recently in
12 and 24 weeks' studies.2 Substituted benzoylamino-
propionic acid 1 (Figure 1) was identified among compounds
with this glucagon receptor antagonistic activity.3
A
radiolabeled material was required for performing preclinical
pharmacokinetics, metabolism, excretion, and quantitative
whole body autoradiography studies, as well as a human
metabolism study. The synthesis of C‐14 labeled compound
1, and its disposition and metabolite profiling in healthy
human subjects is described herein.
Decarboxylative halogenation of carboxylic acids is
known as the Hunsdiecker‐Borodin reaction.5 This reaction
involves the treatment of anhydrous carboxylic acid silver
salts with bromine or iodine and is typically used for decar-
boxylation of aliphatic acids. The reaction was modified,
and its application was extended to some aromatic acids by
2
| RESULTS AND DISCUSSION
2.1 | Synthesis
Molecule 1 was originally synthesized by using a convergent
multistep approach starting from 4‐(carbomethoxy)benzoyl
J Label Compd Radiopharm 2016; 1–6
wileyonlinelibrary.com/journal/jlcr
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
CZESKIS AND SATONIN
be more reactive with cyanide; therefore, conversion of acid 2
into iodide 4 was investigated.
The treatment of acid chloride generated from 2 with
2‐mercaptopyridine N‐oxide sodium salt and iodoform in
the presence of AIBN led to iodide 4 in modest yields (up to
30%). It was noticed that scaling up the reaction resulted in
lower yields of the product, possibly because of instability
of iodoform under high temperature and slow addition
conditions.
The cyanation of iodide 4 by using potassium cyanide
and copper iodide in NMP7 provided nitrile 5 in good yield
(77%). The basic hydrolysis of nitrile 5 into acid 2 required
higher temperature (130°C) and ethoxyethanol as a solvent.
The reaction was not observed in ethanol, whereas attempt
of acidic hydrolysis by heating of nitrile 5 with sulfuric acid
led to the cleavage of benzyl ether.
FIGURE 1 Chemical structure of compound 1
D Barton and coworkers6 who used thiohydroxamic esters as
radical activating groups to expand the scope of the
substrates.
When acid 2 was converted into acid chloride and heated
with 2‐mercaptopyridine N‐oxide sodium salt in the presence
of trichlorobromomethane and azobisisobutyronitrile (AIBN),
no significant reaction was observed. However, when a
solution ofacid chloride in trichlorobromomethane was slowly
added to refluxing suspension of 2‐mercaptopyridine N‐oxide
sodium salt in trichlorobromomethane and 1,2‐dichloroben-
zene, the desired bromide 3 was isolated in 80% yield
(Scheme 3).
An attempt of cyanation of bromide 3 was unsuccessful.
Heating of a mixture 3 with potassium cyanide and copper
iodide in N‐methyl‐2‐pyrrolidinone (NMP)7 provided only
traces of the desired nitrile. It was expected that iodide would
The final steps of forming the peptide bond with β‐alanine
ester by using 2‐chloro‐4,6‐dimethoxytriazine (CDMT)
and N‐methylmorpholine (NMM) followed by basic hydro-
lysis of the coupling product 6 were performed according
to the previously described method3 (Scheme 4).
The synthesis of the radiolabeled material 1‐[14C] was
performed following the method described above. The reac-
tion of iodide 4 with potassium cyanide‐[14C] in the presence
SCHEME 1 Synthesis of nonradiolabeled compound 1

CZESKIS AND SATONIN
3
SCHEME 2 Strategy for radiolabeling of acid 2
SCHEME 3 Bromodecarboxylation of acid 2
SCHEME 4 Synthesis of 1‐[14C]
of copper iodide smoothly gave nitrile 5‐[14C]. The hydroly-
sis of 5‐[14C] with potassium hydroxide in ethoxyethanol at
elevated temperature provided acid 2‐[14C]. Ester 6‐[14C]
was obtained by coupling of β‐alanine ethyl ester with 2‐
[14C] activated by CDMT and NMM. Finally, hydrolysis of
6‐[14C] gave the target compound 1‐[14C] in high total yield
from iodide 4. The material 1‐[14C] was radiochemically
pure, but it contained about 3% of undesired (R)‐enantiomer.
The final purification was accomplished by semipreparative
high‐performance liquid chromatography (HPLC) to provide
the compound with 100% optical purity and 99.2% radio-
chemical purity.
2.2 | Disposition and metabolism8
An open‐label study was conducted in 6 healthy male sub-
jects aged between 22 and 65 years, inclusive, with a body
mass index between 23.1 and 31 kg/m2. The subjects

4
CZESKIS AND SATONIN
received a single 30 mg oral dose containing 100 μCi of com-
pound 1‐[14C], administered as an oral suspension
(consisting of 0.5% ethanol in flat Sprite®). The subjects
were admitted to the Clinical Research Unit on the day before
dosing and remained for up to 17 days.
(0.05 mL). The resultant solution was stirred at room
temperature for 1.5 hours, then evaporated under vacuum,
and re‐evaporated with toluene (2 × 3 mL). The residue
was dried under vacuum for 1.5 hours, then diluted
with toluene (15 mL), and stirred for 10 minutes.
Azobisisobutyronitrile (90 mg, 0.55 mmol) was added,
and the resultant solution was placed on a syringe pump.
In a separate flask, iodoform (1.7 g, 4.32 mmol) was
added to a preheated suspension (approximately 100°C)
of 2‐mercaptopyridine N‐oxide sodium salt (647 mg,
4.34 mmol) in toluene (10 mL). The mixturewas further heated
to reflux (130°C bath), and the above syringe pump solution
was added at 30 mL/hour infusion rate. After addition
was complete, the mixture was refluxed for 5 minutes, then
cooled to room temperature, diluted with hexane (10 mL),
and filtered. The filtrate was evaporated under vacuum
and subjected to ISCO (120 g) chromatography (hexane/
dichloromethane 91:9) to obtain 4 (344 mg, 20%) as a
The disposition of 1 in plasma following a single oral
dose of 1‐[14C] demonstrated a monophasic elimination.
The mean total recovery of radioactivity was 89.4%.
Compound 1 accounted for 91% of total radioactivity present
in plasma. Metabolic profiling and liquid chromatography‐
mass spectrometry analysis of plasma detected only a
single radiolabeled peak 1 at all times analyzed. The major
route of biotransformation for 1 in humans was oxidation of
the t‐butyl group with formation of the primary alcohol
(M12, 67% of dose), followed by a trace amount of sulfate
conjugation of this alcohol (M10, 1.6% of dose) and
elimination in the feces (87.8% of dose recovered in
the feces).
In conclusion, the C‐14 radiolabeled glucagon receptor
antagonist 1‐[14C] was synthesized from the late interme-
diate of the process research and development scheme,
based on decarboxylative iodination reaction. This
approach resulted in a short and efficient synthesis of
the target compound with a total radiochemical yield of
approximately 69%.
Hepatic oxidation followed by a trace amount of sulfate
conjugation and elimination was the main clearance pathway
for compound 1 in humans.
white solid. Thin‐layer chromatography: Rf = 0.36
(hexane/dichloromethane, 90:10). High‐performance liquid
chromatography: Rt = 21 minutes. Nuclear magnetic
resonance (CDCl3, δ, ppm): 1.34 (s, 9H), 1.94 (s, 6H),
2.1 (m, 2H), 2.3 (m, 2H), 5.12 (dd, J = 7.9 and 4.4 Hz,
1H), 6.54 (s, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.14 (d,
J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), and 7.70 (d,
J = 8.3 Hz, 2H).
3.2 | (S)‐4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]benzonitrile, 5
3
| EXPERIMENTAL
A mixture of iodide 4 (319 mg, 0.563 mmol), potassium cya-
nide (42 mg, 0.645 mmol), and copper (I) iodide (62 mg,
0.325 mmol) in NMP (1.1 mL) was heated at 190°C (bath)
for 4.5 hours, then cooled to room temperature, diluted with
water (2 mL), and extracted with diethyl ether (20 mL). The
extract was washed with a mixture of brine (1 mL) and water
(1 mL), dried over sodium sulfate, and evaporated under
vacuum. Biotage (40S) chromatography (elution with
hexane/ethyl acetate 95:5) gave 5 (201 mg, 77%) as a white
solid. Thin‐layer chromatography: Rf = 0.45 (hexane/ethyl
acetate, 90:10). High‐performance liquid chromatography:
Rt = 11 minutes. Nuclear magnetic resonance (CDCl3, δ,
ppm): 1.35 (s, 9H), 1.95 (s, 6H), 2.15 (m, 2H), 2.35 (m,
2H), 5.23 (dd, J = 7.9 and 4.8 Hz, 1H), 6.52 (s, 2H), 6.98
(d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.51 (d,
J = 8.3 Hz, 2H), and 7.68 (d, J = 8.3 Hz, 2H). Mass spec-
trometry (ES+, m/z, %): 466 (100, M + 1).
The nuclear magnetic resonance (NMR) spectra were
obtained on a Varian Mercury‐400 at 400 (1H) and 100
(13C) MHz. Chemical shifts are reported in parts per million
(ppm) downfield from tetramethylsilane. Flash column
chromatography was performed by using Biotage Flash
System. Thin‐layer chromatography (TLC) was conducted
on precoated plates of silica gel 60 F254. High‐performance
liquid chromatography was conducted on a Hitachi instru-
ment with column Zorbax SB‐C8 (4.6 mm × 25 cm);
ultraviolet detection at 230 nm at a flow rate of 1 mL/min;
mobile phase: aqueous 0.1% trifluoroacetic acid/acetonitrile,
20:80. Acid 2 was generated by the acidic treatment of the
corresponding cinchonidine salt. Potassium cyanide‐[14C]
was provided by Tjaden Bioscience. All 14C compounds
were identified by TLC and/or HPLC in comparison with
the corresponding nonradiolabeled isotopomers.
3.1 | (S)‐4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]phenyl iodide, 4
3.3 | (S)‐4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]benzonitrile‐[14C], 5‐[14C]
In the same manner as described above, 5‐[14C] (888 mg, 85%)
was obtained as a white solid starting from iodide 4 (1.267 g,
2.24 mmol), potassium cyanide‐[14C] (56 mCi/mmol,
Oxalyl chloride (1.4 mL, 16.5 mmol) was added dropwise
to a solution of acid 2 (1.501 g, 3.1 mmol) in dichloro-
methane (13 mL), containing dimethylformamide

CZESKIS AND SATONIN
5
150 mCi, 2.68 mmol), and copper (I) iodide (255 mg,
1.34 mmol) in NMP (4.5 mL).
3.7 | Ethyl (S)‐3‐{4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐
4‐yloxy)‐4,4,4‐trifluorobutyl]benzamido‐[carbonyl‐14C]}
propanoate, 6‐[14C]
3.4 | (S)‐4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]benzoic acid, 2
In the same manner as described above, activated intermedi-
ate was prepared, which was treated with β‐alanine ethyl ester
hydrochloride (425 mg, 2.77 mmol) and NMM (430 μL,
3.91 mmol) to obtain 6‐[14C] (1110 mg, 100%) as a white
solid, starting from 2‐[14C] (approximately 1.9 mmol),
CDMT (620 mg, 3.53 mmol), and NMM (525 μL,
4.77 mmol).
A solution of potassium hydroxide (85%, 300 mg, 4.5 mmol)
was added to a mixture of nitrile 5 (300 mg, 0.40 mmol) in
2‐ethoxyethanol (2 mL) in water (0.7 mL). The reaction mix-
ture was stirred at 135°C (bath) for 2.5 hours, then cooled to
room temperature, acidified by addition of 1 N hydrochloric
acid (6 mL), and extracted with ethyl acetate (30 mL).The
extract was washed with brine (2 mL). The combined aque-
ous layers were re‐extracted with ethyl acetate (10 mL). The
combined organic extract was dried over sodium sulfate,
evaporated under vacuum, and re‐evaporated with toluene
(2 × 3 mL) to obtain crude 2 (255 mg), which was used in
the next step without further purification. High‐performance
liquid chromatography: Rt = 7.5 minutes. Nuclear magnetic
resonance (CDCl3, δ, ppm): 1.35 (s, 9H), 1.95 (s, 6H), 2.15
(m, 2H), 2.35 (m, 2H), 5.25 (dd, J = 7.5 and 4.4 Hz, 1H),
6.55 (s, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz,
2H), 7.51 (d, J = 8.3 Hz, 2H), and 8.12 (d, J = 8.3 Hz, 2H).
3.8 | (S)‐3‐{4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]benzamido}propanoic acid, 1
Aqueous sodium hydroxide (5 N, 0.5 mL, 2.5 mmol) was
added to a solution of 6 (204 mg, 0.35 mmol) in tetrahydro-
furan (2.5 mL). The reaction mixture was stirred at room
temperature for 17 hours, acidified by addition of 1 N hydro-
chloric acid (3 mL), and extracted with ethyl ether (30 mL).
The extract was washed with brine (2 mL), dried over sodium
sulfate, and evaporated under vacuum. Biotage (40S) chro-
matography of the residue (eluting with dichloromethane/
ethyl acetate/acetic acid 80:20:1) gave 1 (185 mg, 95%) as a
white solid. Thin‐layer chromatography: Rf = 0.20 (dichloro-
methane/ethylacetate/acetic acid, 80:20:1). High‐performance
3.5 | (S)‐4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐yloxy)‐
4,4,4‐trifluorobutyl]benzoic acid‐[carboxyl‐14C], 2‐[14C]
In the same manner as described above, 2‐[14C] (1.3 g)
was obtained and used in the next step without further
purification starting from 5‐[14C] (888 mg, 1.90 mmol)
in 2‐ethoxyethanol (9 mL) and a solution of potassium hydrox-
ide (85%, 1.25 g, 18.9 mmol) in water (2.9 mL).
liquid chromatography: Rt
=
5.5 minutes. Nuclear
magnetic resonance (CDCl3, δ, ppm): 1.34 (s, 9H), 1.92 (s,
6H), 2.12 (m, 2H), 2.32 (m, 2H), 2.72 (t, J = 7.0 Hz, 2H),
4.17 (q, J = 7.0 Hz, 2H), 5.22 (dd, J = 7.9 and 4.8 Hz, 1H),
6.54 (s, 2H), 6.75 (t, J = 7.0 Hz, 1H), 6.97 (d, J = 8.3 Hz,
2H), 7.36 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), and
7.76 (d, J = 8.3 Hz, 2H).
3.6 | Ethyl (S)‐3‐{4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐
4‐yloxy)‐4,4,4‐trifluorobutyl]benzamido}propanoate, 6
3.9 | (S)‐3‐{4‐[1‐(4′‐tert‐butyl‐2,6‐dimethylbiphenyl‐4‐
yloxy)‐4,4,4‐trifluorobutyl]benzamido‐[carbonyl‐14C]}
propanoic acid, 1‐[14C]
In the same manner as described above, 1‐[14C] (1.04 g, 98%)
was obtained as a white solid starting from 2‐[14C] (1110 mg,
1.9 mmol) in tetrahydrofuran (14 mL) and aqueous sodium
hydroxide (5 N, 3.7 mL, 18.5 mmol).
Part of this material (215 mg) was subjected to prepara-
tive HPLC: column Chiralpack AD‐H 20 × 250 mm; mobile
phase: heptane/2‐propanol/trifluoroacetic acid 90:10:1; flow
rate: 9.0 mL/minute; ultraviolet detection at 230 nm. The
product‐containing fractions were collected at Rt 13 to
16 minutes. The combined fractions were evaporated under
vacuum. A solution of nonradiolabeled 1 (180 mg) in ethyl
acetate (2 mL) was added to the residue. The resultant
solution was evaporated under vacuum and re‐evaporated
with heptane (3 × 3 mL) to give 1‐[14C] (391 mg) as a white
solid; specific activity: 49.5 μCi/mg; optical purity 100%;
radiochemical purity 99.2%.
2‐chloro‐4,6‐dimethoxytriazine (CDMT; 130 mg, 0.74 mmol)
and NMM (110 μL, 1.00 mmol) were added to a solution of 2
(approximately 0.4 mmol) in tetrahydrofuran (4 mL). After
2.5 hours, β‐alanine ethyl ester hydrochloride (90 mg,
0.58 mmol) and NMM (90 μL, 0.82 mmol) were added to
the resultant mixture. The reaction mixture was stirred at
room temperature for 16 hours, then evaporated under
vacuum, and subjected to Biotage (40S) chromatography.
Eluting with hexane/ethyl acetate 63:37 gave 6 (218 mg,
93%) as a white solid. Thin‐layer chromatography: Rf = 0.42
(hexane/ethyl acetate, 60:40). High‐performance liquid chro-
matography: Rt = 8.4 minutes. Nuclear magnetic resonance
(CDCl3, δ, ppm): 1.27 (t, J = 7.0 Hz, 3H), 1.35 (s, 9H),
1.93 (s, 6H), 2.12 (m, 2H), 2.33 (m, 2H), 2.63 (t,
J = 7.0 Hz, 2H), 3.72 (q, J = 7.0 Hz, 2H), 4.17 (q,
J = 7.0 Hz, 2H), 5.22 (dd, J = 7.5 and 4.4 Hz, 1H), 6.54
(s, 2H), 6.84 (t, J = 7.0 Hz, 1H), 6.98 (d, J = 8.3 Hz, 2H),
7.36 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), and
7.77 (d, J = 8.3 Hz, 2H).

6
CZESKIS AND SATONIN
ACKNOWLEDGEMENTS
5. Hunsdiecker H, Hunsdiecker C, Vogt E. Halogen‐containing organic com-
pounds. US Pat 2176181 (1939). Chem Abstr. 1940;34:1685; Hunsdiecker H,
Hunsdiecker C. Degradation of the salts of aliphatic acids by bromine. Ber.
1942;75:291; Borodin A. Ueber Bromvaleriansäure und Brombuttersäure.
Ann. 1861;119:121; Johnson RG, Ingham RK. The degradation of carboxylic
acid salts by means of halogen. The Hunsdiecker reaction. Chem Rev.
1956;56:219; Wilson CV. The reaction of halogens with silver salts of
carboxylic acids. Org React. 1957;9:332.
The authors are grateful to Stan Kolis and Tim White of
Chemical Process Research and Development for the supply
of some intermediates, authentic samples, and experimental
procedures, as well as to Dean Clodfelter and Tammy Priest
of Isotopic Chemistry Group for determination of the specific
activity and optical and radiochemical purities of the final
material. In addition, the authors acknowledge Covance Lab-
oratories for the conduct of the human 14C study.
6. Barton DHR, Lacher B, Zard SZ. Radical decarboxylative bromination of
aromatic acids. Tetrahedron Lett. 1985;26:5939–5942. Barton DHR, Lacher
B, Zard SZ. The invention of radical reactions. Part XVI. Radical
decarboxylative bromination and iodination of aromatic acids. Tetrahedron.
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cyanation of aromatic iodo compounds.
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