Synthesis of the HCV protease inhibitor Vaniprevir (MK-7009) using ring-closing metathesis strategy

Article abstract of DOI:10.1021/jo3001595

Figure Persented: A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.

Full text of DOI:10.1021/jo3001595

Article
pubs.acs.org/joc
Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using
Ring-Closing Metathesis Strategy
Jongrock Kong,* Cheng-yi Chen,* Jaume Balsells-Padros, Yang Cao, Robert F. Dunn, Sarah J. Dolman,
Jacob Janey, Hongmei Li, and Michael J. Zacuto
Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall
yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of
the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing
ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the
diene substrate at a concentration of 0.13 M.
The primary challenges to develop a scalable, cost-effective
synthesis for Vaniprevior (MK-7009) are identifying an efficient
macrocyclization strategy and concise and efficient syntheses of
the key intermediates needed to construct the macrocycle
precursor. Ideally, these key components could be assembled
together in a convergent manner with minimal linear steps. The
first practical synthesis of Vaniprevior (MK-7009) on a large
scale was based on macrolactamization to install the 20-
membered macrocycle.5 The macrocycle precursor 3 was
synthesized via a Heck coupling of two chiral building blocks
(Scheme 1). The process proceeded in 10 linear steps and 21
total steps with 30% overall yield and has served as a practical
means of producing large quantities of Vaniprevior (MK-7009)
to support the safety and clinical studies of this compound.
In recent years, ring-closing metathesis (RCM) has emerged
as a powerful tool for forming macrocyclic compounds.6 This
methodology has been widely used in academic research and
has been shown great promise for large scale pharmaceutical
applications.7 Herein, we report a new synthetic route for
Vaniprevir (MK-7009) based on RCM for the construction of
the 20-membered macrocycle (Scheme 2). We have developed
a practical RCM protocol which employs low catalyst loading
(0.2 mol%) and relatively high concentrations for RCM (0.13
INTRODUCTION
■
Chronic infection with hepatitis C virus (HCV) is a worldwide
epidemic, affecting approximately 180 million individuals
around the globe. HCV is a positive-strand RNA virus of the
flaviviridae family and replicates primarily in the liver. While
disease progression is typically a slow process that occurs over
many years, a significant fraction of patients ultimately develops
serious liver disease, including cirrhosis and hepatocellular
carcinoma.1 Currently, HCV is a leading cause of death in HIV-
coinfected patients and is also the most common indication for
liver transplantation surgery. The existing care for HCV
combines Pegylated Interferon and Ribavirin but only provides
a modest cure rate.2 This low cure rate is partially attributed to
the fact that patient response is highly dependent on the
genotype of the virus. As such, a variety of gene targets have
been evaluated to identify new modes of treatment. The launch
of two new drugs, Boceprevir and Telaprevir, shows promise to
improve the success rate in HCV therapy.3 Despite these
tremendous accomplishments, additional improvements in the
area of genotype coverage, drug dose, and cure rate are still
desired. Vaniprevir (MK-7009) is a potent HCV NS3/4a
protease inhibitor that is being evaluated for the treatment of
HCV at the late stage of clinical studies (Figure 1).4 To ensure
the supply of the drug for ongoing clinical studies, a chemical
process amenable to production of multikilogram quantities of
MK-7009 was required.
Received: January 20, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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Figure 1. HCV NS3/4a protease inhibitors.
Scheme 1. Heck Route for Synthesis of Vaniprevir (MK-7009)5
Scheme 2. RCM Route for Synthesis of Vaniprevir (MK-7009)
M). Efficient synthesis of the key intermediates will also be
described.
more readily available allylic starting material would likely be
more cost-effective as well.
The retrosynthetic analysis of the diene-ester 10 is shown in
Scheme 4. We conceived that diene-ester 10 could be derived
from the coupling of ene-alcohol 13 with the allyl isoindoline
HCl salt 12. The ene-alcohol 13, in turn, could be prepared
from the coupling of the commercially available prolinol ester
14 and ene-acid 15.
As shown in Scheme 3, there are three possible RCM options
for the construction of the macrocycle on the basis of different
positions of olefin metathesis: styryl-homoallyl, allyl-allyl, and
homoallyl-vinyl diene. According to prior results, the use of the
styryl-homoallyl diene 9 for RCM required high catalyst
loading to obtain a satisfactory yield.5 Unfortunately, the
efficiency of RCM with diene 9 could not be improved with a
variation of catalysts and reaction conditions. Hence, this
substrate was not further investigated. We envisioned that the
preparation of allyl-allyl diene 10 would be more straightfor-
ward as compared to that of the homoallyl vinyl substrate 11.
The introduction of two allylic moieties to the diene from a
RESULTS AND DISCUSSION
■
Preparation of Diene-Ester 10. We started the synthesis
of diene-ester 10 by investigation of a cost-effective preparation
of allylisoindoline 12 from bromoisoindoline 18 via a Kumada
coupling reaction using allylmagnesium chloride. The bromoi-
soindoline 18 was previously prepared in four steps from
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Scheme 3. Three Possible Options for RCM Route
Scheme 4. Retrosynthetic Analysis for Allyl−Allyl Diene Synthesis
Scheme 5. Synthesis of Allylisoindoline HCl Salt 12
bromoxylene.5 To develop a more efficient and cost-effective
route for bromoisoindoline synthesis, we started with an
inexpensive starting material, 3-bromobenzonitrile. Hence, the
regioselective deprotonation of 3-bromobenzonitrile at the 2-
position followed by addition of ethyl formate gave rise to
alkoxide intermediate 16. Upon reverse quenching of the
reaction mixture in aqueous media, the alkoxide was readily
converted to hydroxyl lactam 17. Borane reduction of the
hydroxyl lactam followed by HCl salt formation afforded
bromoisoindoline HCl salt 18 in 84% overall yield over two
steps. The bromoisoindoline HCl salt 18 was converted to the
allylisoindoline HCl salt 12 in 90% yield via a one-pot process
employing a Kumada coupling using 2 equiv of allylmagnesium
chloride (Scheme 5).8
The other olefin piece for the diene synthesis was prepared
via carbamate formation between alcohol 199 and tert-leucine
21 (Scheme 6). The alcohol was first activated with DSC to
afford the succinamide intermediate 20. The intermediate is
stable in aqueous media so that the coupling reaction can be
run in aqueous DMF.10 The solubility of tert-leucine in aqueous
DMF was substantially improved, and hence the coupling
reaction proceeded smoothly at ambient temperature to afford
ene-acid 15 in 94% yield. Subsequent EDC-pyridine mediated
coupling of ene-acid 15 with prolinol ester HCl salt 14 afforded
ene-alcohol 13 in 97% yield.11 Activation of the hydroxyl group
with CDI followed by coupling with allylisoindoline HCl 12
completed the synthesis of diene-ester 10 in high overall yield.
Optimization of Ring-Closing Metathesis of Diene
Ester 10. With diene-ester 10 secured, attention was turned
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Scheme 6. Synthesis of Allyl-Allyl Diene
Scheme 7. Catalyst Slow Addition Effect on RCM
toward optimization of the RCM with particular focus on two
aspects of this macrocyclization process. First, the high-dilution
conditions typically employed for RCM presented a severe
limitation for material throughput/volume productivity when
operating at a manufacturing scale. Second, the relatively high
expense of RCM catalysts would necessitate a very low catalyst
loading in order to maintain an economically viable process.
With these challenges in mind, we began study of the RCM
using diene-ester 10 using 1 mol % of the Grubbs−Hoveyda
second-generation catalyst 22 under high-dilution conditions to
gain proof of concept and gauge the catalyst activity. The
reaction, however, only afforded the desired macrocyclic ester 4
in 57% yield after hydrogenation. Increasing the catalyst loading
to 5 mol % only marginally improved the yield to 67%.
Obviously, the reaction called for significant optimization to
achieve high efficiency. Profiling of the RCM reaction showed
that the catalytic activity was very high at the beginning of the
reaction but quickly diminished as the reaction proceeded
further. At the end, many side products including oligomers
were formed. Given this fact, we envisioned that slow addition
of the catalyst may sustain the catalyst activity during the
reaction. Delightfully, this simple modification increased the
yield to 82% when 1 mol % of catalyst was added over 1 h at 60
°C to diene-ester 10 in toluene (50 mL/g of diene) (Scheme
7).
We next shifted our attention to address the common high-
dilution problem associated with macrocyclization by imple-
menting slow addition of the catalyst but at higher reaction
concentration. The reaction run under 30 mL/g of diene (0.058
M), however, afforded the desired 20-membered product 23 in
only 61% yield. The 19-membered macrocyclic ester 24 was
formed in 9% yield as a major side product (Scheme 8). We
postulated that the 19-membered macrocycle was derived from
the RCM of the styryl isomer 25, which in turn was generated
from the isomerization of allylic diene 10 (Scheme 8). It is
known that Ru-H complex generated through decomposition of
the Ru catalyst 22 is responsible for the isomerization of the
olefin.12 This isomerization pathway could be suppressed by
addition of quinone additives which inhibit the decomposition
of the catalyst or suppress Ru-H catalyzed olefin isomer-
ization.13 After screening a few quinone additives,14 we found
that 2,6-dichloroquinone effectively decreased the formation of
the 19-membered ring to <1% without loss of conversion when
the reaction was run at 20 mL/g diene concentration (Table 1,
entry 2). More importantly, the catalyst loading was lowered to
0.2 mol %, which was viable for our large-scale production
(Table 1, entry 3). Continuing studies revealed that higher
temperature positively impacted on RCM to increase the yield
to 84% (Table 1, entry 4).15 Moreover, to suppress undesired
thermodynamic equilibration in the end of the reaction due to a
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Scheme 8. Generation of 19-Membered Macrocycle at Higher Concentration
Table 1. Optimization of RCM with Diene-Ester 10
yield (%)
a
entry amt of 3 (mol %) temp (°C)
additive
method
volume ratio (mL/g diene) concn (M)
23
24
dimers/oligomers
1
2
3
4
5
6
7
70
70
none
A
A
A
A
B
B
C
20
0.086
0.086
0.086
0.086
0.086
0.13
62
72
72
84
88
78
91
8
5
5
0.5
0.2
0.2
0.2
0.2
0.2
2,6-dichloroquinone
2,6-dichloroquinone
2,6-dichloroquinone
2,6-dichloroquinone
2,6-dichloroquinone
2,6-dichloroquinone
20
<1
<1
1.5
70
20
5
100
100
100
100
20
5
20
1.5
2
5
13.5
13.5
>15
5
0.13
2
a
Method A, no additional operation; method B, subsurface N2 gas bubbling; method C, simultaneous addition of diene substrate.
high concentration of ethylene, we attempted to actively
remove the evolving ethylene during RCM by sparging the
reaction mixture with a gentle stream of nitrogen gas. Indeed, a
simple subsurface nitrogen gas bubbling further increased the
yield to 88% (Table 1, entry 5). However, at a higher
concentration (13.5 mL of toluene/g of diene), the yield of the
RCM product was significantly decreased due to the formation
of a high level of dimers and oligomers (Table 1, entry 6). To
circumvent this issue, we decided to mimic high-dilution
conditions by implementing simultaneous slow addition of both
catalyst and diene. Gratifyingly, the efficiency of the reaction
was maintained at a higher concentration (0.13 M, 13.5 mL/g
of diene) to produce the product 23 in 91% yield (Table 1,
entry 7). Hydrogenation of RCM product 23 was conveniently
carried out in a 9:1 mixture of toluene and IPA. A solvent
switch to IPA from a toluene−IPA mixture followed by
crystallization provided the key intermediate, macrocyclic ester
4, in 89% yield with high purity (>99% HPLC purity). It should
also be noted that single crystallization of the macrocyclic ester
from IPA−water resulted in extremely low levels of residual
metals (both ruthenium and palladium content <10 ppm).
With the optimization conditions in hand, we successfully
demonstrated the process of ring-closing metathesis followed
by hydrogenation on a 100 g scale using 0.2 mol % of the
Grubbs−Hoveyda second-generation catalyst at 13.5 mL/g
(0.13 M) concentration in toluene. The demonstration of the
optimized process featuring ring-closing metathesis as a means
for the construction of the macrocycle forms the basis for the
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Scheme 9. Second-Generation RCM Route with Diene-Acid 27
Scheme 10. Synthesis of Vaniprevir (MK-7009)5
development of the manufacturing process of Vaniprevir (MK-
7009).
also serves as the penultimate species for the efficient synthesis
for Vaniprevir (MK-7009).
Synthesis of Vaniprevir (MK-7009). With the availability
of both potassium salt 30 and cyclopropyl sulfonamide 5 as
tosylate,18 direct coupling of both species without salt breaking
of each component was investigated. Delightfully, EDC-
pyridine mediated amidation11 proceeded cleanly to afford
Vaniprevir (MK-7009) in 84% yield with excellent purity after
crystallization from IPAc/heptane (Scheme 10).
Second-Generation RCM Route with Diene-Acid 27.
The sensitivity of the RCM to impurities is a key challenge for
developing a robust manufacturing process.16 The success of
the RCM under low catalyst loading was highly dependent on
the purity of the starting material. The diene-ester 10, on the
other hand, was an oil which limited purification options for
purity upgrade. To reinforce the robustness of our RCM route,
we sought to find a crystalline substrate for RCM. To our
delight, potassium salt 26 was found as a crystalline solid.
Moreover, the potassium salt was conveniently prepared by
treatment of diene-ester 10 with powdered KOH in IPA.17
Upon saponification, potassium salt 26 crystallized sponta-
neously from the reaction media. Treatment of potassium salt
26 with 10% citric acid smoothly converted the salt to free acid
27 and upgraded the purity as well. For example, the purity
could be readily upgraded from ester (<92% HPLC purity) to
salt or free acid (>97% HPLC purity) using these two simple
procedures. The direct use of potassium salt 26 for RCM was
not suitable, due to its poor solubility in organic solvents such
as toluene and IPAc. However, the RCM of diene acid 27
under the conditions defined for diene-ester 10 proceeded
smoothly to produce the desired product, macrocyclic acid 28,
in 91% yield. Subsequent hydrogenation followed by salt
formation afforded potassium salt 30 in 82% yield with
excellent purity upgrade (Scheme 9). The potassium salt 30
CONCLUSIONS
■
In summary, we have defined and developed a highly efficient
synthesis of Vaniprevir (MK-7009) featuring ring-closing
metathesis (RCM) of a fully elaborated diene. The synthesis
proceeds with the longest sequence of nine steps, combining
four important components, tert-leucine unit 15, hydroxy
proline unit 14, isoindoline unit 12, and cyclopropyl amino acid
side chain 5. Simultaneous slow addition of the ruthenium
catalyst and the diene substrate enables the ring-closing
metathesis for the construction of a 20-membered ring to
proceed at low catalyst loading (0.2 mol %) without employing
high-dilution conditions. The strategy was successfully applied
to the efficient synthesis of Vaniprevir (MK-7009).
EXPERIMENTAL SECTION
Chemical reagents were used as received from suppliers. NMR spectra
were taken on 400 or 500 MHz spectrometers. High-resolution mass
spectra (HRMS) were obtained on a Fourier transform ion cyclotron
■
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resonance (FTICR) mass spectrometer and are reported as m/z
(relative intensity). Accurate masses are reported for the molecular ion
(M + 1).
with overhead stirring was charged with ene-acid 15 (335 g, 1.23 mol)
and MeCN (1 L). To this was added trans-4-hydroxy-L-proline methyl
ester hydrochloride (256.6 g, 96 wt % contaminated with 4% of
carboxylic acid, 1.36 mol). Pyridine (146.5 g, 1.85 mol) was added via
addition funnel over 45 min. The resulting slurry was aged for 1 h.
EDC·HCl (319.5 g, 1.667 mol) was then added as a solid. The
resulting solution was warmed to 45 °C and stirred at that
temperature. (Note: the ene-acid starting material was not detected by
HPLC after 4 h.) The reaction was inversely quenched into a 6 L
extractor with overhead stirring and a drop valve that had been
charged with 2.0 L of 15 wt % aqueous citric acid and 2.5 L of toluene.
The biphasic mixture was stirred for 30 min, and then stirring was
stopped. The aqueous layer was discarded. The extractor was charged
with 0.5 L of 15% aqueous NaCl (half brine), and the resulting
biphasic mixture was stirred for 30 min. The aqueous layer was
discarded, and theorganic layer was collected. The organic phase was
concentrated to ∼2 L and then dried via azeotrope with toluene (50
°C bath and 45−50 mmHg pressure) under constant-volume
conditions. The final total volume was adjusted to 3.5 L. This solution
was transferred via in-line filtration to a separate vessel. The resulting
solution was measured to have KF = 100 ppm of H2O. The toluene
stream was assayed to contain 475.5 g of ene-alcohol 13 (97% yield).
1H NMR (400 MHz, CDCl3): δ 5.78−5.67 (m, 1H), 5.49 (d, J = 12.0
4-Bromoisoindoline Hydrochloride 18. To a 500 mL round-
bottom flask equipped with a magnetic stirrer, thermocouple, and
nitrogen inlet was added diisopropylamine (8.61 mL, 60.4 mmol) and
then THF (50 mL). The solution was cooled to −20 °C. n-BuLi (24.1
mL of 2.50 M in hexane, 60.4 mmol) was slowly added. The resulting
solution was aged over 5 min at −20 °C and then cooled to −70 °C.
In the meantime, 3-bromobenzonitrile (10.0 g, 54.9 mmol) was
dissolved in THF (20 mL) at room temperature. The 3-
bromobenzonitrile solution in THF was transferred to LDA solution
while controlling the temperature below −65 °C. The resulting
solution was aged over 5 min around −70 °C. Then the reaction was
quenched with ethyl formate (6.04 mL, 74.2 mmol). The resulting
solution was aged over 5 min at −70 °C. The reaction solution was
reversely quenched into 50 mL of water in ice bath. After quenching
was completed, 50 mL of EtOAc was added. The resulting solution
was acidified to pH 4 using concentrated HCl (9 mL). The aqueous
layer was extracted with EtOAc (2 × 50 mL). Concentration of the
combined organic layers under reduced pressure provided 11.67 g of
the desired product. Without further purification, the crude lactam (5
g, 21.93 mmol) was dissolved in toluene (20 mL). The resulting
solution was heated to 55 °C. Borane ethyl sulfide complex (4.58 mL,
48.2 mmol) was slowly added to the reaction solution for 10 min.
After addition, the reaction mixture was heated to 110 °C and aged
overnight at 110 °C. The reaction mixture was cooled to around 75 °C
and quenched by adding 5 N HCl in IPA (10 mL). The resulting
slurry was aged over 1 h at 75 °C. Finally, the slurry was cooled to
room temperature and aged at that temperature over 30 min. The
slurry was filtered, and the wet cake was washed with two 10 mL
portions of toluene. After overnight drying of the wet cake under
vacuum with N2 gas sweep, 4.32 g of compound 18 was obtained as an
off-white solid (84% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.15
(br s, 2H), 7.59 (d, J = 10.0 Hz, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.35
(d, J = 10.0 Hz, 1H), 4.63 (s, 2H), 4.48 (s, 2H). 13C NMR (125 MHz,
DMSO-d6): δ 137.9, 136.0, 131.6, 131.2, 122.9, 116.8, 51.6, 51.6. The
NMR data match literature values.5
(S)-2-((((2,2-Dimethylpent-4-en-1-yl)oxy)carbonyl)amino)-
3,3-dimethylbutanoic Acid (Ene-Acid 15). A 1 L round-bottom
flask was charged with DMF (270 mL), alcohol 19 (44 g, 0.385 mol),
DSC (109 g, 0.424 mol), and pyridine (6.21 mL, 0.077 mol) at room
temperature. The resulting solution was heated to 45−50 °C and aged
until the amount of starting material was <2.0% (ca. 1 h). The reaction
mixture was cooled to 5 °C, and water (270 mL) was slowly added
while controlling the temperature below 10 °C. After addition, the
mixture was stirred for 30 min. L-tert-Leucine (50.60 g, 0.385 mol) was
added to the reaction mixture in one portion and then NaHCO3 was
added in four portions. (Note: upon adding solid NaHCO3, carbon
dioxide (CO2) gas was generated. To avoid the vigorous CO2 gas
generation, slow addition of NaHCO3 was needed. NaHCO3 can be
replaced by K3PO4.) The reaction mixture was aged at 15−25 °C over
12 h. A 450 mL amount of heptane was added. The layers were
separated, and the organic layer was discarded. The aqueous layer was
acidified to around pH 1−2 by adding 3 N HCl (ca. 500 mL) at
around 20 °C. The acidic aqueous layer was extracted with 450 mL of
IPAc. The organic layer was washed with two 450 mL portions of
water. The organic solvent was removed under reduced pressure. Ene-
acid 15 was obtained as a white solid (97 g, 94% yield). 1H NMR (500
MHz, CDCl3, mixture of two rotamers): δ 11.10 (br s, 1H), 6.26 and
5.27 (d, J = 9.5 Hz, 0.3H and d, J = 6.0 Hz, 0.7H), 5.83−5.75 (m, 1H),
5.06−5.00 (m, 2H), 4.21 and 3.97 (d, J = 9.5 Hz, 0.7H and d, J = 6.0
Hz, 0.3H), 3.85 (d, J = 10.5 Hz, 1H), 3.79 (d, J = 10.5 Hz, 1H), 2.02
(d, J = 7.5 Hz, 2H), 1.04 (s, 9H), 0.91 (s, 6H). 13C NMR (125 MHz,
CDCl3): δ 176.5, 156.6, 134.4, 117.6, 72.98, 62.0, 43.4, 34.6, 34.3, 26.5,
24.0. HRMS (ESI+): exact mass calcd for [M + 1]+ (C14H26NO4) m/z
272.1856, found m/z 272.1871.
Hz, 1H), 5.00−4.95 (m, 2H), 4.60 (t, J = 8.0 Hz, 1H), 4.46 (br s, 1H),
4.23 (d, J = 12.0 Hz, 1H), 3.80−3.76 (m, 2H), 3.72−3.70 (m, 1H),
3.71 (s, 3H), 2.29 (dd, J = 12.0, 8.0 Hz, 1H), 1.99−1.92 (m, 3H), 0.99
(s, 9H), 0.84 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 172.7, 171.0,
157.1, 134.5, 117.7, 73.1, 70.2, 59.2, 58.0, 56.6, 52.3, 43.5, 37.6, 35.9,
34.3, 26.4, 24.7, 24.1. HRMS (ESI+): exact mass calcd for [M + 1]+
(C20H35N2O6) m/z 399.2490, found m/z 399.2505.
(3R,5S)-1-((S)-2-((((2,2-Dimethylpent-4-en-1-yl)oxy)-
carbonyl)amino)-3,3-dimethylbutanoyl)-5-(methoxycarbonyl)-
pyrrolidin-3-yl 4-Allylisoindoline-2-carboxylate (Diene-Ester
10). A 10 L three-neck flask with overhead stirring was charged
with the ene-alcohol 13 (475.5 g, 1.193 mol) as a solution in toluene
(3.5 L total volume), followed by a 75 mL toluene rinse. 1,1′-
Carbonyldiimidazole (CDI; 223 g, 1.372 mol) was charged into the
ambient-temperature (Ti = 22 °C) solution, followed by a 5 mL
toluene rinse. The resulting solution was aged at 22−26 °C for 1 h.
Formation of the CDI adduct was monitored by HPLC by conversion
to the corresponding carbamate. (Note: 0.1 mL of the reaction was
added to 0.5 mL of BuNH2 neat, and the resulting solution was heated to
50 °C for 2−3 min. This solution was then diluted to 10 mL and assayed
by HPLC.) After 1 h, over 99% conversion was observed. A 450 mL
portion of H2O was then added to the reaction solution, and the
resulting biphasic solution was aged for 1 h. 4-Allylisoindoline·HCl
(285 g, 98 wt %, 1.46 mol) was then added as a solution in H2O (1.95
L). The resulting biphasic solution was heated to 50 °C and aged at 50
°C for 10 h. The phases were allowed to settle, and HPLC assay of the
organic phase showed that conversion was over 99%. The aqueous
phase (pH 7−8) was separated and discarded. The organic phase was
washed with 1.0 L of 15 wt % aqueous citric acid below 25 °C. The
organic phase was washed with 0.5 L of 5 wt % aqueous NaHCO3.
The organic phase was concentrated to ∼1.4 L total volume
(conditions: 50 mmHg pressure and T = 35 °C). The final volume
was adjusted to make an approximately 50 wt % stock solution for the
next step, RCM. Diene-ester 10 was obtained as a 50 wt % solution in
toluene (662 g, 95% yield). 1H NMR (500 MHz, CDCl3): δ 7.19 (dd,
J = 15.0, 5.0 Hz, 1H), 7.10−7.01 (m, 2H), 5.91−5.82 (m, 1H), 5.69−
5.61 (m, 1H), 5.35 (br s, 1H), 5.31 (dd, J = 10.0, 5.0 Hz, 1H), 5.04
(dd, J = 25.0, 15.0 Hz, 2H), 4.95 (dd, J = 30.0, 20.0 Hz, 2H), 4.76−
4.50 (m, 5H), 4.24 (dd, J = 10.0, 5.0 Hz, 1H), 4.16 (t, J = 12.5 Hz,
1H), 3.90−3.83 (m, 1H), 3.72 (s, 3H), 3.63 (dd, J = 25.0, 10.0 Hz,
1H), 3.33−3.25 (m, 3H), 2.49 (dd, J = 15.0, 10.0 Hz, 1H), 2.22 −2.11
(m, 1H), 1.89−1.81 (m, 2H), 1.02 (s, 9H), 0.73 (d. J = 5.0 Hz, 6H).
13C NMR (125 MHz, CDCl3, mixture of two rotamers): δ 172.1 and
172.1, 171.3 and 171.2, 156.8 and 156.7, 153.9, 136.9 and 136.6, 135.6,
135.5 and 135.4, 134.8, 134.6 and 134.5, 128.1 and 128.1, 127.8 and
127.7, 120.6 and 120.5, 117.5, 116.6 and 116.5, 73.5 and 73.5, 72.6 and
72.6, 59.2 and 59.1, 58.0 and 57.9, 54.1 and 53.6, 52.8, 52.4 and 52.3,
(2S,4R)-Methyl 1-((S)-2-((((2,2-Dimethylpent-4-en-1-yl)oxy)-
carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrroli-
dine-2-carboxylate (Ene-Alcohol 13). A 2 L round-bottom flask
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51.5 and 51.1, 43.3, 37.7 and 37.4, 35.6 and 35.4, 35.1 and 35.0, 34.1,
26.3, 24.0 and 23.9. HRMS (ESI+): exact mass calcd for [M + 1]+
(C32H46N3O7) m/z 584.3330, found m/z 584.3347.
solution of KOH pellets that had been dissolved in i-PrOH (0.3 L) was
added dropwise while controlling the temperature below 30 °C. The
solution was aged at ambient temperature. After 16 h, the slurry was
filtered and the wet cake was washed with 400 mL of i-PrOH. The
cake was dried via vacuum suction under a N2 tent. A 96.0 g amount of
compound 26 was obtained as a white solid (92% yield, 98.2 HPLC
Ring-Closing Metathesis with Diene-Ester 10 (RCM Product
23). In a 3 L round-bottom flask equipped with a magnetic stirrer,
thermocouple, nitrogen inlet, and reflux condenser was added 2,6-
dichloroquinone (3.03 g, 0.0173 mol) and degassed toluene (1.03 L).
In the meantime, we prepared the diene-ester 10 stock solution (200
g, 0.171 mol, 50 wt % in toluene) and Grubbs−Hoveyda-II catalyst
stock solution by dissolving the catalyst (0.215 g, 0.343 mmol) in 100
mL of toluene. A 10 vol % amount of diene-ester 10 stock solution was
charged into the reaction solution. The resulting solution was heated
over 100 °C with gentle N2 gas bubbling through the solution.
Grubbs−Hoveyda-II catalyst stock solution in toluene and the
remaining 90 vol % of diene-ester 10 stock solution were slowly and
simultaneously added to the reaction solution over 1 h. After the
addition was completed, the reaction mixture was stirred for 1 h more
to achieve the complete consumption of diene-ester substrate. The
reaction mixture was cooled to room temperature and assayed (86.4 g,
91% yield). The crude reaction mixture was carried over to the next
step.
Hydrogenation of RCM Product 23. The RCM product 23
(86.4 g, 0.1556 mol) in toluene (1.35 L) was transferred to a shaker
can. The remaining RCM product was rinsed with two 75 mL portions
of IPA and transferred to a shaker can. The catalyst 5% Pd/C-Shell (25
g, 25 wt %) was charged. The reaction vessel was purged three times
with nitrogen gas followed by three purges of hydrogen gas at 45 psi.
The reaction mixture was aged for 24 h under 45 psi of hydrogen.
After 24 h, the reaction was stopped and the heterogeneous solution
was transferred to a 1 L plastic container. The shaker was rinsed with
two 30 mL portions of toluene/IPA (9/1), and this solution was
combined with the main solution. The catalyst was filtered through
Sloka Floc (20 wt %). The pad was washed with two 30 mL portions
of toluene/IPA (9/1) mixed solvent (30 mL). The crude macrocyclic
ester 4 in toluene/IPA (9/1) was carried over to the crystallization
step (4.26 wt % in toluene/IPA (9/1)).
Purification/Crystallization of Mac-Ester 4. The solvent was
switched to IPA. The IPA solution (460 mL) was heated to 45 °C and
aged at 45 °C over 15 min. A 60 mL portion of water was slowly added
to the IPA solution over 30 min at 45 °C, and the resulting solution
was further stirred over 15 min. At that point, 10 mg of Mac-ester (0.1
wt %) was charged as a seed. Once crystallization started, the batch
was cooled to 40 °C and aged over 15 min at that temperature. A
second portion of water (60 mL) was added over 1 h at 40 °C. The
slurry was cooled to room temperature slowly over 1 h and then aged
overnight at room temperature. The slurry was further cooled to 0 °C
and aged over 1 h at 0 °C. The slurry was filtered and washed with 100
mL of precooled IPA/water (2/1 at 0 °C). The solid was dried over 24
h at 45 °C under vacuum with an N2 sweep. A 77.5 g amount of the
desired macrocyclic ester 4 was obtained as a white solid (89% for
hydrogenation followed by crystallization, 81% yield over two steps
from diene-ester 10; >99% HPLC purity; Ru <10 ppm and Pd <10
ppm). 1H NMR (500 MHz, CDCl3): δ 7.20 (dd, J = 10.0, 5.0 Hz, 1H),
7.08 (d, J = 10.0 Hz, 1H), 7.04 (d, J = 5.0 Hz, 1H), 5.53 (d, J = 5.0 Hz,
1H), 5.31 (t, J = 5.0 Hz, 1H), 4.71 (dd, J = 25.0, 15.0 Hz, 2H), 4.62 (t,
J = 10.0 Hz, 1H), 4.54−4.48 (m, 2H), 4.42 (t, J = 10.0 Hz, 2H), 4.13
(d, J = 15.0 Hz, 1H), 3.81 (d, J = 15.0 Hz, 1H), 3.75 (s, 3H), 3.24 (d, J
= 15.0 Hz, 1H), 2.76−2.72 (m, 1H), 2.54−2.48 (m, 1H), 2.43−2.37
(m, 1H), 2.14 (dq, J = 15.0, 5.0 Hz, 1H), 1.53−1.43 (m, 2H), 1.33−
1.25 (m, 3H), 1.20−1.11 (m, 1H), 1.50 (s, 9H), 0.95 (s, 3H), 0.78 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 172.0, 170.7, 156.2, 153.4,
137.5, 136.1, 134.9, 127.9, 127.5, 120.2, 74.1, 72.4, 59.0, 57.5, 54.0,
52.4, 52.2, 50.8, 36.8, 36.5, 35.4, 34.0, 33.5, 30.6, 26.2, 25.0, 23.7, 23.3.
The NMR data match literature values.5
1
purity). H NMR (500 MHz, CD3COOD, mixture of rotamers): δ
7.27−7.23 (m, 1H), 7.18−7.10 (m, 1.8H), 7.05 (dd, J = 10.0, 3.0 Hz,
0.1H), 6.90 (dd, J = 10.0, 6.0 Hz, 0.1H), 5.97−5.87 (m, 1H), 5.87−
5.80 (m, 0.2H), 5.73−5.67 (m, 0.8H), 5.45 (d, J = 2.5 Hz, 1H), 5.11−
4.91 (m, 3H), 4.83 −4.58 (m, 5H), 4.48−4.37 (m, 2H), 4.07 (t, J =
12.5 Hz, 0.2H), 3.88 (ddd, J = 15.0, 12.5, 5.0 Hz, 0.8H), 3.62 (ddd, J =
30.0, 30.0, 10.0 Hz, 0.8H), 3.36−3.22 (m, 3H), 2.79−2.75 (m, 0.2H),
2.68−2.64 (m, 0.8H), 2.52−2.45 (m, 0.2H), 2.36−2.30 (m, 0.8H),
2.07−2.03 (m, 1H), 1.92−1.83 (m, 2H), 1.80 (s, 7.9H), 1.05 (s, 1.1H),
0.92 (s, 1.3H), 0.74 (s, 4.7H). 13C NMR (125 MHz, CDCl3, mixture
of rotamers): δ 176.6, 173.9 and 173.8, 158.8 and 158.8, 155.7, 137.9
and 137.5, 136.6 and 136.5, 136.5 and 136.3, 135.8 and 135.6, 135.6
and 135.5, 129.1 and 129.0, 128.6 and 128.4, 121.5 and 121.4, 117.9,
117.0 and 116.8, 75.5 and 75.5, 73.5, 60.7 and 60.7, 59.3 and 59.2,
55.6, 53.3 and 53.1, 52.1 and 51.9, 43.8 and 43.8, 38.3 and 38.2, 36.0
and 35.8, 35.5 and 35.5, 34.9 and 34.7, 26.7, 24.1, and 24.0. HRMS
(ESI+): exact mass calcd for [M + 1]+ (C31H43KN3O7) m/z 608.2733,
found m/z 608.2756.
(2S,4R)-4-((4-Allylisoindoline-2-carbonyl)oxy)-1-((S)-2-((((2,2-
dimethylpent-4-en-1-yl)oxy)carbonyl)amino)-3,3-
dimethylbutanoyl)pyrrolidine-2-carboxylic Acid (Diene-Acid
27). A 3 L flask with overhead stirring and a drop valve was charged
with the solid diene K salt 26 and toluene. An aqueous solution of
citric acid (15 wt %) was then added. The resulting biphasic solution
was aged for 1 h with stirring at 25 °C. The aqueous phase was
drained, and the organic phase was washed with 100 mL of water. The
aqueous phase was drained and discarded. The resulting toluene
stream was maintained as a 1000 mL solution and dried via azeotrope
by distillation with toluene under constant-volume conditions (35 °C
at 50 mmHg pressure) in order to meet the specification of KF ≤300
ppm. The toluene stream was transferred to a smaller vessel via in-line
filtration and then concentrated to a 50 wt % solution in toluene. The
diene-acid stock solution in toluene was directly used for RCM.
Ring-Closing Metathesis with Diene-Acid 27. A 500 mL three-
neck round-bottom flask with overhead stirring and a reflux condenser
was charged with 2,6-dichloro-1,4-benzoquinone (217 mg, 1.229
mmol) and toluene (200 mL) at room temperature. The reaction
solution was then heated over 100 °C with gentle nitrogen gas
bubbling. In the meantime, we prepared the diene-acid 27 stock
solution (40.0 g, 30.68 mmol, 50 wt % in toluene) and Grubbs−
Hoveyda-II catalyst stock solution by dissolving the catalyst (44 mg,
0.07 mmol) in 20 mL of toluene. Then 6 mL of diluted diene-acid
stock solutioin (10 vol %) was added into the reaction vessel. The
catalyst stock solution was transferred to a 20 mL syringe and set in a
syringe pump. Grubbs−Hoveyda-II catalyst stock solution in toluene
and the remaining 90 vol % of diene-acid stock solution was slowly and
simultaneously added to the reaction solution for 1 h. After the
addition of catalyst was complete, the reaction mixture was aged for an
additional 30 min to achieve >98% conversion. The reaction mixture
was cooled to room temperature. The toluene solution (270 mL, 13.5
mL/1 g of diene-acid) including cis/trans mixtures of RCM products
was carried over to the next step without further purification (17.3 g,
91% yield, 7.2 wt % in toluene).
Hydrogenation of RCM Product 28. The RCM prduct 28 in
toluene (17.3 g, 7.2 wt % in toluene) was transferred to a shaker can.
The remaining RCM-acid was rinsed with two 15 mL portions of IPA
and transferred to the shaker can. A 5% Pd/C-Shell catalyst (4.98 g, 30
wt %) was charged. The reaction vessel was purged three times with
nitrogen gas followed by three purges of hydrogen gas at 45 psi. The
reaction mixture was aged under 45 psi of hydrogen. After 24 h, the
reaction was stopped and the heterogeneous solution was transferred
to a 1 L plastic container. The shaker was rinsed with two 30 mL
portions of mixed solvent (Tol/IPA 9/1), and this solution was
combined with the main batch. The heterogeneous solution was
Potassium (2S,4R)-4-((4-Allylisoindoline-2-carbonyl)oxy)-1-
((S)-2-((((2,2-dimethylpent-4-en-1-yl)oxy)carbonyl)amino)-3,3-
dimethylbutanoyl)pyrrolidine-2-carboxylate (Diene-Acid K
Salt 26). A 2 L three-neck flask with overhead stirring and an
addition funnel was charged with diene-ester 10 (100 g, 171.4 mmol)
as a solution in i-PrOH (0.8 L total volume, 0.7 L of i-PrOH). A
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Article
filtered through Sloka Floc (4 g, 20 wt %). The pad was washed with
two 30 mL portions of toluene/IPA (9/1) mixed solvent. The crude
macrocyclic acid 29 in toluene/IPA (9/1) was carried over to the
crystallization step (4.26 wt % in toluene/IPA (9/1)).
Butcher, J. W.; Carroll, S. S.; DiMuzio, J.; Fandozzi, C.; Gilbert, K. F.;
Mao, S.-S.; McIntyre, C. J.; Nguyen, K. T.; Romano, J. J.; Stahlhut, M.;
Wan, B.-L.; Olsen, D. B.; Vacca, J. P. J. Am. Chem. Soc. 2008, 130,
4607.
Isolation of Mac-Acid K Salt 30. The crude macrocyclic acid 29
(4.0 g, 7.36 mmol) in toluene/IPA (9/1) was concentrated. The
solvent was switched to EtOH. The final volume of EtOH was
adjusted to make about 8 mL (2 mL of EtOH/g of macrocyclic aicd
29). KOH stock solution (418 mg, 7.45 mmol of KOH in 3.5 mL of
EtOH) was slowly added to the reaction solution over 2 h. The
resulting thick slurry was heated to 45 °C over 1 h. The slurry was
slowly cooled to ambient temperature. The resulting slurry was aged
overnight at ambient temperature. The slurry was filtered, and the wet
cake was washed with 6 mL of EtOH. The cake was dried under
vacuum with N2 sweep. A 3.49 g amount of macrocyclic acid K-salt 30
was obtained as a white solid (82% yield over two steps from RCM
product 28). 1H NMR (500 MHz, CD3Cl): δ 7.19 (dd, J = 7.5, 7.7 Hz,
1H), 7.07 (d, J = 10.0 Hz, 1H), Hz, 1H), 7.02 (d, J = 10.0 Hz, 1H),
5.53 (d, J = 5.0 Hz, 1H), 5.21 (br s, 1H), 4.68 (dd, J = 30.0, 15.0 Hz,
2H), 4.49 (d, J = 10.0 Hz, 1H), 4.39 (d, J = 10.0 Hz, 1H), 4.18 (dd, J =
10.0, 5.0 Hz, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1H),
3.46 (br s, 1H), 3.23 (d, J = 10.0 Hz, 1H), 2.63 (dd, J = 15.0, 10.0 Hz,
1H), 2.50−2.37 (m, 2H), 2.21−2.15 (m, 1H), 1.50−1.42 (m, 2H),
1.38−1.28 (m, 3H), 1.21−1.10 (m, 1H), 0.98 (s, 9H), 0.97 (s, 3H),
0.81 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 177.9, 170.4, 156.2,
153.8, 137.5, 136.4, 135.1, 127.9, 127.4, 120.1, 74.9, 72.6, 61.1, 58.9,
54.5, 52.4, 50.8, 36.8, 36.0, 34.1, 33.6, 30.8, 26.3, 25.2, 23.8, 23.3.
HRMS (ESI+): exact mass calcd for [M + 1]+ (C29H40KN3O7) m/z
582.2576, found m/z 582.2593.
(4) Jensen, D. N. Engl. J. Med. 2011, 364, 1272.
(5) Song, Z. J.; Tellers, D. M.; Journet, M.; Kuethe, J. T.; Lieberman,
D.; Humphrey, G.; Zhang, F.; Peng, Z.; Waters, M. S.; Zewge, D.;
Nolting, A.; Zhao, D.; Reamer, R. A.; Dormer, P. G.; Belyk, K. M.;
Davies, I. W.; Devine, P. N.; Tschaen, D. M. J. Org. Chem. 2011, 76,
7804.
(6) (a) Grubbs, R. H. Handbook of Metathesis; Wiley: Weinheim,
Germany, 2003. (b) Hoveyda, A. H.; Zjugralin, A. R. Nature 2007,
450, 243. (c) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.
(d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490. (e) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
́
2199. (f) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2005,
44, 4490. (g) Abell, A. D.; Alexander, N. A.; Aitken, S. G.; Chen, H.;
Coxon, J. M.; Jones, M. A.; McNabb, S. B.; Muscroft-Taylor, A. J. Org.
Chem. 2009, 74, 4354.
(7) (a) Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.;
Senanayake, C. H. Org. Procss Res. Dev. 2009, 13, 250. (b) Yee, N. K.;
Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang,
X.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang,
L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Sinelli, E. M.;
Johnson, M.; Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye,
P.; Samstag, W. J. Org. Chem. 2006, 71, 7133−7145. (c) Nicola, T.;
Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9,
513. (d) Poirier, M.; Aubry, N.; Boucher, C.; Ferland, J. M.; LaPlante,
S.; Tsantrizos, Y. S. J. Org. Chem. 2005, 70, 10765. (e) Shu, C.; Zeng,
X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina,
V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303−1306. (f) Wang, H.;
Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M., Jr. Org.
Process Res. Dev. 2008, 12, 226.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H NMR and 13C NMR spectra of compounds
(8) Zacuto, M. J.; Shultz, C. S.; Journet, M. Org. Process Res. Dev.
2011, 15, 158.
4, 10, 13, 15, 18, 26, and 30. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) Chen, G.; Ma, X. S.; Guan, Z. J. Am. Chem. Soc. 2003, 125, 6697.
(10) Li, H.; Chen, C. Y.; Balsells-Padros, J. Synlett 2011, 10, 1454.
(11) Chen, C. Y.; Frey, L. F.; Shultz, C. S.; Wallace, D. J.;
Marcantonio, K.; Payack, J. F.; Vazquez, E.; Springfield, S. A.; Zhou,
G.; Liu, P.; Kieczykowski, G. R.; Chen, A. M.; Phenix, B. D.; Singh, U.;
Strine, J.; Izzo, B.; Krska, S. W. Org. Process Res. Dev. 2007, 11, 616.
(12) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jongrock_kong@merck.com; cheng_chen@merck.
com
■
Notes
The authors declare no competing financial interest.
(13) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(14) See the Supporting Information.
(15) RCM at 100 °C without quinone additive produced more than
15% of 19-membered macrocyclic side product.
(16) Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W.
M., Jr. Org. Process Res. Dev. 2008, 12, 226.
(17) The use of powdered KOH minimized H2O in the reaction
media, thereby ensuring a high recovery of water-soluble potassium
salt 25.
(18) Belyk, K. M.; Bangping, X.; Bulger, P. G.; Leonard, W. R. J.;
Balsells-Padros, J.; Yin, J.; Chen, C. Y. Org. Process Res. Dev. 2010, 14,
692.
ACKNOWLEDGMENTS
■
We thank our colleagues at Merck Research Laboratories:
Michel Journet, Bangping Xiang, Zhiguo J. Song, David M.
Tellers, Mathew Maust, Lisa DiMichele, Charles W. Ross, and
David M. Tschaen for their support of this project.
REFERENCES
(1) Lavanchy, D. Liver Int. 2009, 29, 74 (Suppl. 1).
(2) Fellay, J.; Thompson, A. J.; Ge, D.; Gumbs, C. E.; Urban, T. J.;
Shianna, K. V.; Little, L. D.; Qiu, P.; Bertelsen, A. H.; Watson, M.
Nature 2010, 464, 405.
■
(3) (a) McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.; Nguyen, K. T.;
Romano, J. J.; Butcher, J. W.; Gilbert, K. F.; Bush, K. J.; Holloway, M.
K.; Swestock, J.; Wan, B.-L; Carroll, S. S.; DiMuzio, J. M.; Graham, D.
J.; Ludmerer, S. W.; Mao, S.-S; Stahlhut, M. W.; Fandozzi, C. M.;
Trainor, N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. J. Med. Chem.
2010, 53, 2443. (b) Holloway, M. K.; Liverton, N. J.; Ludmerer, S. W.;
McCauley, J. A.; Olsen, D. B.; Rudd, M. T.; Vacca, J. P.; McIntyre, C. J.
HCV NS3 Protease Inhibitors; U.S. Patent 7,470,664, 2008.
(c) Liverton, N. J.; Carroll, S. S.; DiMuzio, J. M.; Fandozzi, C.;
Graham, D. J.; Hazuda, D. J.; Holloway, M. K.; Ludmerer, S. W.;
McCauley, J. A.; McIntyre, C. J.; Olsen, D. B.; Rudd, M. T.; Stahlhut,
M.; Vacca, J. P. Antimicrob. Agents Chemother. 2010, 54, 305.
(d) Liverton, N. J.; Holloway, M. K.; McCauley, J. A.; Rudd, M. T.;
3828
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