Synthesis of deuterium-, tritium-, and carbon-14-labeled BILN2061, a potent hepatitis C virus protease inhibitor

Article abstract of DOI:10.1002/jlcr.940

Hepatitis C virus (HCV) serine protease is a target for antiviral therapy against HCV infection, a leading cause of liver transplantation in the US. BILN2061, (1S, 4R, 65, 7Z, 145, 18A)-14-cyclopentyloxycarbonylamino-18-[2-(2- isopropylamino-thiazol-4-yl)

Full text of DOI:10.1002/jlcr.940

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 447–455.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.940
Research Article
Synthesis of deuterium-, tritium-, and carbon-14-
labeled BILN2061, a potent hepatitis C virus protease
inhibitor
Bachir Latli1,*, Matt Hrapchak1, Vida Gorys2, Carl A. Busacca1 and
Chris Senanayake1
1 Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals,
Research and Development Center, 900 Ridgebury Road, Ridgefield, CT 06877, USA
2 Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., Research and
Development, 2100 Cunard Street, Laval, Que., Canada H7S 2G5
Summary
Hepatitis C virus (HCV) serine protease is a target for antiviral therapy against HCV
infection, a leading cause of liver transplantation in the US. BILN2061, (1S, 4R,
6S, 7Z, 14S, 18R)-14-cyclopentyloxycarbonylamino-18-[2-(2-isopropylamino-thiazol-
4-yl)-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-
ene-4-carboxylic acid, is a potent inhibitor of HCV and the first compound in this
class of cyclic peptides in human trials. Here, we report the synthesis of deuterium-
labeled BILN2061 with isotopic enrichment of 99%, tritium-labeled BILN2061 with a
specific activity of 17.1 GBq/mmol, and carbon-14-labeled BILN2061 with a specific
activity of 1.83 GBq/mmol. The isotopes were incorporated via a Hantzsch thiazole
synthesis of labeled isopropyl thiourea and a-bromoketone intermediate. The
preparation of labeled isopropyl thiourea is reported. Copyright # 2005 John Wiley
& Sons, Ltd.
Key Words: HCV; BILN2061; deuterium; tritium; carbon-14
Introduction
Since it was identified in 1989, hepatitis C virus (HCV) has been viewed as the
major cause of chronic hepatitis in humans.1 Globally, 3% of the world
population is infected with this virus. Interferon or a combination of interferon
and ribavirin, are the only approved therapies for treatment of HCV infections.
However, these therapies suffer from low efficacy and various side effects.2 The
*Correspondence to: Bachir Latli, Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Research and Development Center, 900 Ridgebury Road, Ridgefield, CT 06877, USA.
E-mail: blatli@rdg.boehringer-ingelheim.com
Copyright # 2005 John Wiley & Sons, Ltd.
Received 18 January 2005
Revised 9 February 2005
Accepted 11 February 2005

448
B. LATLI ET AL.
other treatment is liver transplantation for a few lucky patients. Therefore a lot
of effort has been concentrated on the discovery and development of new and
selective drugs to prevent and treat HCV-related diseases.
The HCV-encoded NS3 serine protease is essential for viral replication
in vivo, and consequently, it is a good target for antiviral therapy against
HCV.3–5 An extensive search for potent inhibitors of this protease led to the
discovery of novel macro-cyclic tripeptides with nanomolar cellular potency
and an adequate oral pharmacokinetic profile in animals.
BILN2061 is the first of this class of compounds to reach human trials.
Administration of BILN2061 to patients infected with HCV genotype 1 for
2 days resulted in an impressive reduction of HCV RNA plasma levels.6–9 The
goal of this work was to prepare labeled BILN2061 with stable and radioactive
isotopes to support research, drug metabolism and pharmacokinetics studies.
Results and discussion
BILN2061 is a tripeptide molecule, with a 15-member ring, five stereo
centers, and a cyclic cis-double bond. The synthesis of this compound included
(among many manipulations), preparation of a substituted cyclopropyl-amino
acid, a quinoline-thiazole moiety, and ring closure metathesis.10 The
quinoline-thiazole moiety was considered to introduce stable and radioactive
isotopes on BILN2061 to simplify the synthesis. The classical Hantzsch
thiazole synthesis has been used extensively to prepare substituted thiazoles
from the condensation of a-halo-ketones and N-monosubstituted thioureas.11
The mechanisms of this reaction have been studied in detail.12 For example,
under neutral conditions, the 2-(N-substituted amine)thiazoles are exclusively
formed. The regioselectivity can be altered to give both the 2-substituted and
the 3-substituted-2-imino-2,3-dihydrothiazoles under acidic conditions.13
As shown in Scheme 1, the preparation of [2H7]-isopropylthiourea was
accomplished by first treating benzoyl chloride with potassium thiocyanate in
acetone. The isothiocyanate thus produced was then treated in situ with [2H7]-
isopropylamine (99.2 at% D) to give the benzoylthiourea intermediate in 80%
yield. Hydrolysis of this benzoylthiourea with aqueous sodium hydroxide gave
[2H7]-isopropylthiourea in 72% yield after crystallization from hexane: ethyl
acetate.14,15 Deuterated isopropylthiourea was then condensed with the
a-bromoketone (5) ((1S, 4R, 6S, 14S, 18R)-18-[2-(2-bromoacetyl)-7-met-
hoxyquinolin-4-yloxy]-14-cyclopentyloxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid methyl ester) at 708C in
isopropanol to give the substituted thiazole in 98% yield. This material was
then hydrolyzed with a solution of LiOH in THF/methanol at room
temperature to give [2H7]-BILN2061 in 91% yield (Scheme 2).
The same approach was used to prepare tritium-labeled BILN2061 using
tritium-labeled isopropylamine ([2-3H]-isopropylamine, prepared by ARC by
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O
Cl
a
c
b
O
S
CD3
CD3
O
S
14C
O
S
T
N
N
N
N
N
H
N
D
H
H
H
H
H
d
d
d
S
CD3
CD3
S
14C
S
T
N
H2N
D
H2N
N
H
H2N
H
N
H
(1)
72%
(3)
(2)
54%
52%
Scheme 1. Synthesis of labeled isopropylthiourea. (a) KSCN, acetone [2H7]-
isopropylamine; (b) KSCN, acetone, [2-3H]-isopropylamine; (c) KS14CN,
acetone, isopropylamine; (d) aqueous 10% NaOH
tritium gas reduction of acetone oxime) in 17% overall yield. Thus, tritium-
labeled isopropylamine with a specific activity of 25 Ci/mmol was diluted with
unlabeled isopropylamine and used to prepare tritium-labeled isopropyl
thiourea in 54% radiochemical yield. Coupling as seen before to the a-
bromoketone (5) followed by ester hydrolysis gave [3H]-BILN2061 with a
specific activity of 462 mCi/mmol.
For the synthesis of [14C]-BILN2061, initial consideration was given to the
carbamate-capping group. Carbon-14 atom may be introduced into this
moiety if [14C]-phosgene is used to prepare the cyclopentyl-carbamoyl
chloride. However, concerns over the stability of the carbamates in vivo
prevented the pursuit of this route. The focus was then shifted to parts of the
molecule which are less susceptible to metabolism. As seen before in the
synthesis of [2H7]- and [3H]-BILN2061, the quinoline-thiazole part was built
into the molecule from a reaction of a-bromoketone-quinoline intermediate (5)
and isopropylthiourea. The radiosynthesis required the preparation of [14C]-
isopropylthiourea, with the carbon-14 atom preferably in the urea and not on
the isopropyl side chain, due to the fact that 2-alkylaminothiazoles are prone
to metabolic cleavage to aminothiazoles. So to prepare [14C]-labeled
isopropylthiourea, [14C]-potassium thiocyanate with a specific activity of
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B. LATLI ET AL.
O
Br
O
N
O
O
H
N
O
N
O
O
NH
O
O
(5)
d,b
c,b
a,b
S
S
S
H
N
H
H
14C
N
N
N
O
O
N
O
N
O
N
N
N
CD
3
CD
D
T
3
O
O
O
O
O
H
H
H
O
N
O
N
O
N
N
O
N
O
N
O
O
O
O
NH
NH
NH
OH
OH
OH
O
O
O
[3H]-BILN2061
[
14C]-BILN2061
[2H7]-BILN2061
72%
31%
89%
Scheme 2. Synthesis of labeled BILN2061. (a) isopropanol, (1), 708C; (b) LiOH,
THF/water/MeOH, rt; (c) isopropanol, (2), 708C; (d) isopropanol, (3), 708C; (e)
isopropanol, (4), 708C
50 mCi/mmol was reacted with benzoyl chloride giving benzoyl isothiocya-
nate, which was trapped with isopropylamine in acetone to give N-benzoyl-N0-
isopropylthiourea as reported above. Hydrolysis with a 10% aqueous sodium
hydroxide solution gave the desired [14C]-labeled isopropylthiourea in more
than 50% radiochemical yield (Scheme 1). Reaction of [14C]-isopropylthiourea
with the a-bromoketone (5) in isopropanol with heating at 708C gave the
quinoline-thiazole derivative (referred to as BILN2061 methyl ester) in 76%
radiochemical yield. Simple hydrolysis of the methyl ester to the acid using
lithium hydroxide in a mixture of methanol, tetrahydrofuran and water gave
[14C]-BILN2061 in 95% yield and with a specific activity of 49.58 mCi/mmol
(Scheme 2). [14C]-BILN2061 was stored neat at ꢀ808C or as a dilute ethanolic
solution at ꢀ208C for up to 3 months with little decomposition.
Experimental procedures
Materials and methods
All radioactive experiments were carried out in the radiosynthesis laboratory
in hoods dedicated to carbon-14 or tritium syntheses only. Weighing
operations were performed on a Mettler MTS microbalance (calibrated
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and checked for accuracy every 6 months). Liquid scintillation counting
was accomplished using a Beckman LS5000TA and ready safeTM
cocktail (Beckman, Fullerton, CA). Radio-TLC was carried out on a
BIOSCAN System 200 imaging scanner using an auto-changer 1000 and
WinScan software version 2.1a (Bioscan Inc., Washington, DC). The
quantification of the HPLC chromatograms was carried out using an
HPLC system comprised of a radiomatic A515 Flo-one\Beta radioactivity
flow detector (Packard Instrument Company, Meriden, CT), two
pumps (HITACHI L-6200A intelligent pump), a linear UVIS 200, Ultima
FloTM AP cocktail (Packard, Meriden, CT), and radiomatic 500TR V 3.60
for data evaluation. The analytical HPLC purity verification was carried out
on a Zorbax SB-C18 column, particle size 5 mm, 4.6 ꢁ 150 mm, and the
column was fitted with an OPTI-Guard C18 column guard (1.0 mm). UV
detection was at 220 nm. Mobile phase: A (water), B (acetonitrile),
both solvents contain TFA (10 mM). Gradient: 20–100% B in 30 min,
then back to 20% B in 5 min and hold for 2 min at 20% B. Evaporation of
solvents and non-radioactive volatile components was accomplished at
reduced pressure using Buchi rotary evaporator unless stated otherwise.
¨
Mass spectra for non-radioactive compounds were acquired by a Hewlett-
Packard auto sampler Series 1100, connected to a Micromass Platform
LCZ in the ES mode. NMR spectra were recorded with a Bruker
400 MHz DPX spectrometer using deuterated chloroform as a solvent and
tetramethyl silane as the internal standard unless stated otherwise.
Melting points are uncorrected and were obtained using MEL-TEMP1 3.0
(Laboratory Devices, Inc., USA). Pre-coated TLC sheets (silica gel 60 F254
)
and silica gel 60–200 Mesh (Nominal, I.D., grade 62) for flash chro-
matography, were obtained from EM Science (Gibbstown, NJ). [2H7]-
isopropylamine with 99.2at% D, was from CDN, Pointe Claire, Que.,
Canada. Tritium-labeled isopropylamine was purchased from ARC, Saint
Louis, MO with a specific activity of 25 Ci/mmol. [14C]-Potassium thiocyanate
was obtained from Moravek Biochemicals & Radiochemicals Inc. with a
specific activity of 50 mCi/mmol. Isopropylthiourea was purchased from
Lancaster Synthesis. The rest of the reagents were purchased from Aldrich
Chemicals Company.
Non-radioactive synthesis
Synthesis of [2H7]-isopropylthiourea (1). To a solution of potassium
thiocyanate (1.47 g, 15.13 mmol) in acetone (30 ml) was added benzoyl
chloride (1.67 ml, 14.37 mmol) at 08C under nitrogen atmosphere. The
resulting cloudy solution was stirred for 90 min at this temperature before
the ice-bath was removed and [2H7]-isopropylamine (99.2at% D, 1.0 g,
15.13 mmol) was added via syringe. The mixture was further stirred at room
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temperature for another 90 min, and then poured into an Erlenmeyer flask and
water was added to give a fluffy white solid. This solid was filtered, washed
with water and dried under reduced pressure to give 2.618 g of the N-benzoyl-
1
N0-isopropylthiourea as a white solid. H-NMR (CDCl3) d: 10.60 (brs, 1H),
8.91 (brs, 1H), 7.83 (d, J ¼ 8:20 Hz, 2H), 7.62 (dt, J ¼ 8:20, 1.14 Hz, 1H), 7.51
(t, J ¼ 8:20 Hz, 2H). MS-ES+: m/z 230.1 (MH+, 50%), MS-ES-: m/z 228
(Mꢀ, 20%). A mixture of this derivative (2.6 g, 11.34 mmol) in 10% aqueous
NaOH (40 ml), was heated to reflux for 30 min to give a colorless solution.
After cooling to 608C, it was extracted with ethyl acetate. The combined
extracts were dried over MgSO4, filtered and concentrated in vacuo to remove
most of the solvent. Hexane was then added to give a fluffy white precipitate,
which was filtered, washed with hexane, and dried under reduced pressure to
give 1.02 g of product in 72% yield. 13C-NMR (DMSO-d6) d: 181.82, 44.64
(m), 20.96 (m). MS-ES+: m/z 126 (MH+, 100%). Mp ¼ 161–1638C.
Synthesis of [2H7]-BILN2061 methyl ester. A solution of [2H7]-isopro-
pylthiourea (50 mg, 0.4 mmol), (5) (252.5 mg, 0.33 mmol) in isopropyl alcohol
(4 ml) was stirred at 708C in a preheated oil bath for 3 h. After cooling to room
temperature, the solution was concentrated in vacuo. The residue was dissolved
in chloroform and washed with a saturated aqueous NaHCO3 (2 ꢁ 60 ml),
brine (100 ml), dried over MgSO4, filtered and concentrated under reduced
pressure. The yellow residue was purified by flash column chromatography to
1
give 310 mg of a white solid. H-NMR (CDCl3) d: 7.98 (d, J ¼ 9:10 Hz, 1H),
7.47 (s, 1H), 7.38 (brs, 2H), 7.05 (dd, J ¼ 9:10, 2.43 Hz, 1H), 6.99 (s, 1H), 5.54
(m, 1H), 5.39 (m, 2H), 5.24 (t, J ¼ 9:60 Hz, 1H), 5.18 (s, 1H), 5.03 (m, 1H),
4.90 (m, 1H), 4.62 (t, J ¼ 7:34 Hz, 1H), 4.31 (d, J ¼ 11:45 Hz, 1H), 4.06 (m,
1H), 3.94 (s, 3 H), 3.68 (s, 3 H), 3.06 (m, 1H), 2.39 (m, 1H), 2.16–2.24 (m, 3 H),
1.85–1.93 (m, 2H), 1.60–1.84 (m, 11H), 1.56 (m, 2H), 1.42 (m, 3 H). MS-ES+:
m/z 796.5 (MH+, 100%), MS-ES-: m/z 794.3 (M-, 100%).
Synthesis of [2H7]-BILN2061. A solution of [2H7]-BILN2061 methyl ester
(270 mg, 0.34 mmol) in THF (8 ml) and methanol (4 ml), was added a solution
of lithium monohydrate in water (114 mg, 4 ml). The resulting mixture was
stirred at room temperature overnight. Then, most of the solvents were
removed under reduced pressure to obtain a white paste. To this, were added
water (5 ml) and brine (2 ml) followed by aqueous 1 N HCl solution until
pH ¼ 6. The solution was extracted with ethyl acetate and the combined
extracts were dried over MgSO4, filtered and concentrated in vacuo to give
1
241 mg of a yellow solid. H-NMR (CDCl3) d: 10.01 (brs , 1H), 7.96 (d,
J¼ 9:08 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 7.11 (d, J¼ 9:08 Hz,
1H), 6.39 (s, 1H), 5.48–5.60 (m, 2H), 5.11 (m, 1H), 5.09 (m, 1H), 4.78 (d,
J¼ 7:87 Hz, 1H), 4.65 (m, 1H), 4.28 (m, 1H), 3.95 (s, 3 H), 3.76 (m, 1H), 2.90
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(m, 1H), 2.45 (m, 1H), 2.30 (m, 1H), 2.14 (m, 1H), 1.75–2.00 (m, 9H), 1.60–
1.75 (m, 4 H), 1.41–1.60 (m, 4 H), 1.25–140 (m, 4 H). MS-ES: m/z 782.4 (MH+,
100%), MS-ES-: m/z 780.2 (M-, 100%). HPLC, Rt ¼ 16:00, 99.3%.
Radiosynthesis
Synthesis of [3H]-BILN2061. A batch of [3H]-BILN2061 was prepared in an
analogous fashion to the deuterium-labeled material starting from [3H]-
isopropylamine. To a solution of KSCN in acetone (0.5 ml) was added benzoyl
chloride (4.8 ml, 41.1 mmol) at 08C. After stirring at this temperature for 2 h, the
ice-bath was removed and a solution of [3H]-isopropylamine (70 mCi, 25 Ci/
mmol, 2.8 mmol) in toluene (1 ml) was added. The resulting mixture was stirred
at room temperature for 3 h before unlabeled isopropylamine (3.25 ml,
38.3 mmol) was added and the mixture was stirred overnight. Most of the
solvents were removed under reduced pressure and the residue was dissolved in
10% aqueous NaOH (1 ml) and heated to 100–1108C for 30 min. The solution
was cooled to 60–708C and extracted with ethyl acetate (3 ꢁ 2 ml). The
combined extracts were concentrated under a stream of nitrogen then under
reduced pressure for 3 h. The residue was dissolved in ethanol (2 ml) to afford a
stock solution of [3H]-isopropylthiourea (2) (39 mCi, 56% radiochemical
yield). [3H]-Isopropylthiourea (38 mCi) was taken on to afford a total of
11.9 mCi of [3H]-BILN2061 with a specific activity of 462 mCi/mmol. Radio-
HPLC: Rt ¼ 16:20 (97.46%).
Synthesis of [14C]-BILN2061. Acetone (2 ml) was added to a vial containing
[14C]-potassium thiocyanate (50 mCi, specific activity ¼ 50 mCi=mmol,
1.0 mmol). The resulting solution was cooled to 08C in an ice-bath before
benzoyl chloride (110 ml, 0.95 mmol) was added in one portion via syringe. The
cloudy mixture was further stirred at this temperature for 1.5 h, then the ice-
bath was removed and isopropylamine (85.2 ml, 1.0 mmol) was added quickly.
The mixture was stirred at room temperature for 1.5 h. Water (10 ml) was
added to give a fluffy white solid. The solid was filtered and transferred to a
new reaction vial using acetone. Acetone was removed under reduced pressure
and the residue was treated with 10% aqueous NaOH (3 ml) and heated to
1108C for 30 min. The clear solution was cooled to 408C and extracted with
ethyl acetate. The combined extracts were concentrated under a stream of
nitrogen to about 1.0 ml, and then n-hexane was added slowly to give a fluffy
white solid. Most of the solvents were removed and the remaining solid was
dried in vacuo to give 62 mg of [14C]-isopropylthiourea (3) as a white solid in
52% chemical yield. [14C]-BILN2061 methyl ester was obtained as described in
the non-radioactive synthesis from [14C]-isopropylthiourea (62 mg, 0.52 mmol)
and (5) (384.5 mg, 0.5 mmol). The product was isolated by flash chromato-
graphy purification as a white solid (319 mg) with a specific activity of
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49.58 mCi/mmol and a total radioactivity of 20 mCi. The product elutes with
cold BILN2061 methyl ester on TLC (10% MeOH/CHCl3) and HPLC: Rad-
detection, Rt ¼ 17:90 min (99%); UV detection, Rt ¼ 17:55 min (99%).
Hydrolysis of this methyl ester (315 mg, 0.4 mmol) as seen before, gave
309 mg of a yellow solid in 95% chemical yield or 19.0 mCi with a specific
activity of 49.58 mCi/mmol. The product elutes with cold BILN2061 on
HPLC: Rad-detection, Rt ¼ 16:00 min (99%); UV detection, Rt ¼ 15:65 min
(99%). 1H-NMR using double encapsulation of both this material and a non-
radioactive sample of BILN2061 (similar concentrations in CDCl3) were
identical.
Conclusion
Deuterium- and tritium-labeled BILN2061 was prepared in 64 and 17%
overall yield, respectively, from the commercially available [2H7]-isopropyla-
mine or [2-3H]-isopropylamine. Carbon-14-labeled BILN2061 was prepared in
37% overall radiochemical yield starting from commercially available [14C]-
potassium thiocyanate to incorporate the radioactive carbon in the thiazole
ring. The syntheses were efficient and straightforward.
Acknowledgements
We wish to thank Dr Montse Llinas-Brunet, Dr Murray D. Bailey and Dr
Pierre Beaulieu for experimental details; and Mr Scott Leonard for help with
NMR of radioactive compounds.
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