A rapid, large-scale synthesis of a potent cholecystokinin (CCK) 1R receptor agonist

Article abstract of DOI:10.1021/op800176e

The development of a scalable synthesis of a potent cholecystokinin (CCK) IR receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support

Full text of DOI:10.1021/op800176e

Organic Process Research & Development 2008, 12, 1201–1208
A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor
Agonist
Jeffrey T. Kuethe,* Karla G. Childers, Guy R. Humphrey, Michel Journet, and Zhihui Peng
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, U.S.A.
Abstract:
deliveries of API that support safety assessment and pharma-
cological studies may rely upon modifications to the existing
route. Modifications that address liabilities such as low-yielding
transformations, the use of potentially dangerous reagents and
reaction conditions, and elimination of chromatography are
examined and then implemented. The rapid development of a
scalable synthesis of 1 aptly illustrates this approach.
The development of a scalable synthesis of a potent cholecystokinin
(CCK) 1R receptor agonist is described. The focus on a rapid
short-term delivery rather than longer-term development allowed
for the preparation of multihundred gram quantities to support
aggressive timelines and evaluate safety and pharmacological
studies. Key improvements involved streamlining the preparation
of imidazole acid 7 and discovery of a more efficient preparation
of naphthyl piperazine fragment 23, including an improved
preparation of 3-bromonaphthallic anhydride 16.
Introduction
Cholecystokinin (CCK) is a gastrointestinal hormone and
neurotransmitter that induces satiety by direct stimulation of
vagal afferents that signal to feeding centers in the brain. There
are two G-protein-coupled seven transmembrane receptors
associated with the physiological actions of CCK: CCK1R and
CCK2R (also known as CCKA and CCKB receptors, respec-
tively). CCK1R is predominately located in the periphery and
is believed to be the primary mediator of satiety, while CCK2R
is mostly expressed in the brain. Shown to inhibit food intake
in many species including humans,1 CCK1R agonists have been
studied as satiety agents for the treatment of obesity.2 Recently,
Merck & Co., Inc. identified a number of potent and selective
CCK1R agonists for the potential treatment of obesity, and
compound 1 was selected for preclinical development to fully
define safety and pharmacological properties.3 In recent years,
the increased pace of drug discovery has led to a corresponding
increase in the pace of preclinical development. Key to the
successful initiation of preclinical programs with well-defined
and accelerated timelines is the ability of process chemists to
deliver required amounts of development candidates in a timely
manner. In the fast-paced environment of drug development,
the development of a long-term manufacturing route is typically
not required in the initial stages of a program, and rapid first
The original synthesis of 1 employed by the Medicinal
chemistry group involved 13 chemical steps (longest linear
sequence 10 steps) and required 6 chromatographic purifications
including reverse phase chromatography of 1 (Schemes 1-3).3
Fortunately, the synthesis was convergent and 1 was obtained
from two key intermediates: imidazole acid 7 (Scheme 1) and
naphthyl piperazine 13 (Scheme 2). The preparation of 7 began
with the condensation of 2 with 3 in the presence of NaHMDS
to give benzamidine 4. Direct reaction of 4 with ethyl bro-
mopyruvate 5 in refluxing 1,4-dioxane afforded imidazole ester
6, which was purified by chromatography. Saponification of
the ester then gave imidazole acid 7 in 50% overall yield. The
synthesis of 13 started with 3-nitro-1,8-naphthoic anhydride 8
and involved the use of stoichiometric HgO to provide 3-ni-
tronaphthoic acid 9 in 59% yield (Scheme 2). Conversion of 9
to the corresponding ester (95%) was followed by reduction of
the nitro group to give naphthyl amine 10 (95%) as an unstable
intermediate. Treatment of 10 with sodium nitrite in 48% HBr
and subsequent heating to 95 °C in the presence of CuBr under
standard Sandmeyer reaction conditions furnished bromide 11
in 70% yield. Cross-coupling of 11 with N-Boc-piperazine 12
under standard Buchwald cross-coupling conditions4 and depro-
tection of the product with TFA gave 13 in 50% yield. The
overall yield of 13 was 19% from commercially available 8.
The preparation of 1 from intermediates 7 and 13 in the
initial route involved activation of 7 with MsCl in the presence
of 1-methyl-imidazole followed by reaction with 12 to give 14,
which was purified by silica gel chromatography.5 Saponifica-
tion of the methyl ester with LiOH provided 1 in 70% yield
after purification by reverse phase chromatography. The initial
* Author for correspondence. E-mail: jeffrey_kuethe@merck.com.
(1) For leading references, see: (a) Little, T. J.; Horowitz, M.; Feinle-
Bisset, C. Obes. ReV. 2005, 6, 297. (b) Moran, T. H.; Kinzig, K. P.
Am. J. Physiol. Gastrointest. LiVer Physiol. 2004, 286, G183. (c)
Chandra, R.; Little, T. J. Curr. Opin. Endocrinol. Diabetes Obes. 2007,
14, 63. (d) Dufresne, M.; Seva, C.; Fourmy, D. Physiol. ReV. 2006,
86, 805.
(2) For leading references, see:(a) Szewczyk, J. R.; Laudeman, C. Curr.
Top. Med. Chem. 2003, 3, 837. (b) Garc´ıa-Lo´pez, M. T.; Gonza´lez-
Mun˜iz, R.; Mart´ın-Mart´ınez, M.; Herranz, R. Curr. Top. Med. Chem.
2007, 7, 1180.
(3) Berger, R.; Zhu, C.; Hansen, A. R.; Harper, B.; Chen, Z.; Holt, T. G.;
Hubert, J. A.; Lee, S. J.; Pan, J.; Qian, S.; Reitman, M. L.; Strack,
A. M.; Weingarth, D. T.; Wolff, M. S.; MacNeil, D. J.; Weber, A. W.;
Edmondson, S. D. Bioorg. Med. Chem. Lett. 2008, 18, 4833.
(4) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
(5) Ueki, H.; Ellis, T. K.; Martin, C. H.; Boettiger, T. U.; Bolene, S. B.;
Soloshonok, V. A. J. Org. Chem. 2003, 68, 7104.
10.1021/op800176e CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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Scheme 1. Initial synthesis of imidazole acid 7
Scheme 2. Initial synthesis of naphthyl piperazine 13
Scheme 3. Final steps in initial synthesis of 1
synthesis involved 10 linear steps and proceeded in 13% overall
yield. Although the chemistry utilized in Schemes 1-3 for the
synthesis of 1 appeared to be straightforward, several liabilities
needed to be addressed prior to scale-up. The preparation of
imidazole acid 7 was in reasonable shape, and only process
improvements including elimination of chromatography and
finding suitable conditions to improve the yields and efficiency
were required. On the other hand, the preparation of naphthyl
piperazine 13 required more attention due to the length of the
synthesis and the reported instability of 10. Specific problems
that needed to be addressed in the short term also included the
long reaction times with HgO (4 days) for the preparation of 9,
insertion of the bromide via diazonium chemistry in the
preparation of 11, and the extremely unreliable cross-coupling
of 11 with 12, where yields were reported to fluctuate between
10-50%. Finally, the coupling of 7 and 13 at the final stages
of the synthesis needed to be improved to streamline the process
and allow for the isolation of 1 without recourse to chromato-
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Scheme 4
Scheme 5
graphic purification. To meet the aggressive delivery timelines,
a strategy was rapidly developed that allowed for the preparation
of 1 on multihundred gram scale. In this manuscript we outline
an improved preparation of 1 that was utilized for the short-
term delivery.
After stirring for 2 h, the reaction was made acidic with 2 N
HCl and extracted with IPAc, and the product 7 was crystallized
from IPAc/heptane in analytically pure form and in 75% overall
yield from 2.
Naphthyl Piperazine. Given the liabilities mentioned above
regarding the initial synthesis of 13, our efforts were focused
on overhauling this route. To avoid the low-yielding and
potentially hazardous diazonium chemistry of the unstable
aniline intermediate 10, a new synthesis of bromide 11 was
required. The deceptively simple structure of 11 masks the fact
that 1,3-disubstituted naphthalenes are difficult to prepare via
standard directing rules for naphthalenes. Fortunately recent
reports by Moseley and co-workers7 appeared outlining the
preparation of bromo ester 11 that closely followed an earlier
synthesis (Scheme 5).8 Bromination of readily available naph-
thalic anhydride 15 with 0.75 equiv of bromine in 70%
concentrated nitric acid occurred regioselectively in the 3-posi-
tion of the naphthalene ring to give 16 in 17% yield. Any
Imidazole Acid. The preparation of 7 followed the initial
synthesis outlined in Scheme 1; however, the process was
completely optimized as a through-process where 7 was the
only isolated product (Scheme 4). For example, reaction of
m-phenetidine 2 (1.0 equiv) with NaHMDS (1.1 equiv) in THF
at 3-5 °C followed by the addition of p-tolunitrile 3 and
warming to room temperature resulted in quantitative conversion
to 4 in <1 h. After dilution with MTBE and water, the layers
were separated, and the MTBE stream was carried forward
without further purification. The HPLC assay yield of 4 was
98% after workup. The crude MTBE stream containing 4 was
then solvent switched from MTBE to 1,4-dioxane, ethyl
bromopyruvate 5 (1.2 equiv) and solid NaHCO3 (2.5 equiv)
were added, and the mixture was heated to an internal
temperature of 95-97 °C for 2 h.6 After dilution of the crude
reaction mixture with MTBE and water, the layers were
separated, and the MTBE stream was carried forward without
further purification. The HPLC assay yield of 6 was 90% after
aqueous workup. The MTBE stream containing 6 was solvent
switched to THF, and MeOH and NaOH (2 equiv) were added.
(6) 1,4-Dioxane proved to be the superior solvent for this reaction and
was selected for use in the short term despite its toxicological
properties.
(7) (a) Moseley, J. D.; Moss, W. O. Org. Process Res. DeV. 2003, 7, 53.
(b) Moseley, J. D.; Moss, W. O.; Welham, M. J.; Ancell, C. L.;
Banister, J.; Bowden, S. A.; Norton, G.; Young, M. Org. Process Res.
DeV. 2003, 7, 58.
(8) (a) Rule, H. G.; Thompson, S. B. J. Chem. Soc. 1937, 1764. (b)
Whitmore, F. C.; Fox, A. L. J. Am. Chem. Soc. 1929, 51, 3363.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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Scheme 6
attempts by the authors to improve the yield of 16 were
unsuccessful. Mercury acetate-mediated decarboxylation in the
presence of NaOH/HgO/AcOH gave predominately the desired
1,3-isomer 18 but also produced significant amounts of the
corresponding 1,6-isomer 17. After an acidic quench to liberate
the organo-mercury intermediates, 17 and 18 were isolated as
a 3:1 mixture in 97% combined yield. Recrystallization from
acetic acid gave pure 18 in 58-61% overall yield from 16.
Conversion of acid 18 to bromo ester 11 was accomplished in
97% yield by esterification in MeOH with 0.5 equiv of
concentrated sulfuric acid.
In evaluation of this reported route, our primary concern was
the low-yielding bromination of 15, and our first goal was to
examine alternative methods for the preparation of 3-bro-
monaphthalic anhydride 16. The bromination procedure de-
scribed in the literature was never seriously considered because
of extremely low yields and reported instability of waste streams
that were prone to gassing.6 A number of conditions were
rapidly investigated for the conversion of 15 to 16 that involved
numerous solvent systems and brominating agents (Br2, NBS,
dibromodimethylhydantoin). After extensive experimentation,
it was discovered that optimal conditions involved reacting 15
with dibromodimethylhydantoin (DBDMH) in concentrated
sulfuric acid between -5 and 0 °C for 1 h and allowing the
reaction mixture to warm to room temperature overnight
(Scheme 6).9 The resulting reaction mixture was inversely
quenched into water, and the resulting slurry was filtered to
provide 16 consistently in 80% HPLC assay yield. Also detected
in the crude isolated solid were unreacted starting material 15
(7%), dibromide 19 (10%), and an unidentified dibromoisomer
20 (2%). Recrystallization of the crude mixture from DMF/
water (10:1) furnished 16 in 70% overall yield from 15 while
also reducing the overbrominated byproduct 19/20 to <5%. The
level of these impurities was subsequently demonstrated not to
be detrimental to the downstream chemistry as they were
effectively removed.
in Scheme 5 with only slight modifications. While the use of
stoichiometric mercury presented environmental concerns, we
accepted the fact that disposal of mercury waste was reliable
on the scale intended for the first delivery. Since the first
delivery required only several hundred grams of 1, the
controversial decision was made to use mercury for the
preparation of 11, while recognizing that this would never be
considered for pilot-plant scale or for full-scale manufacturing.
Mercury acetate mediated decarboxylation of 16 in the presence
of NaOH/HgO/AcOH gave a mixture of organo-mercury
intermediates that were hydrolyzed with concentrated HCl in a
one-pot process to provide a 3:1 mixture of 18/17 in near
quantitative yield. The bromo acid mixture at this point was
found to be contaminated with 5500-8500 ppm Hg. Recrys-
tallization from acetic acid provided 18 in 56% overall yield
from 16. The recrystallization of 18 lowered the Hg level to
∼1200 ppm Hg. The presence of Hg at this level required
careful control in subsequent transformations and was carefully
tracked (vida infra) to provide API with acceptable levels of
heavy metals. The esterification of 18 was conducted in MeOH
at 65 °C for 18 h in the presence of 0.5 equiv of sulfuric acid
and was followed by an aqueous workup and extraction of the
product into EtOAc/hexane. The crude organic stream contain-
ing 11 was treated with Darco G60 to further lower the Hg
level, filtered, and concentrated to provide 11 in 89% yield (99
wt %, 742 ppm Hg).
The coupling of 11 and Boc-piperazine 12 in the original
synthesis was extremely unreliable with yields never exceeding
50%, and this reaction required extensive optimization of all
the reaction parameters to enable the reaction to be carried out
in a reproducible manner. The original coupling was carried
out in the presence of Pd2(dba)2 and ligand 21 in the presence
of NaO-tBu as the base in toluene or dioxane at 85 °C for 18 h.
Efforts aimed at identifying other catalyst/ligand systems in the
short time frame in which this research was conducted proved
unfruitful. Therefore, we elected to optimize this reaction in
terms of catalyst/ligand loading, base, solvent, and temperature.
Initial experiments rapidly identified that when all of the
reagents were added together and heated to 75-85 °C, variable
results were obtained and conversions were typically low
With an effective method for the preparation of 16 in hand,
conversion of 16 to bromo ester 18 was conducted as described
(9) Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery,
T.; Bachert, D. J. Org. Chem. 2003, 68, 3695.
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Scheme 7
(35-75%). However, when the catalyst and ligand were
premixed prior to the addition of 11 and 12, more consistent
results were obtained. The optimal conditions for the coupling
of 11 and 12 involved premixing the catalyst (Pd2(dba)3, 2.5
mol %), ligand 21 (3 mol%), and powdered anhydrous K3PO4
(3.00 equiv) in 2-methyltetrahydrofuran (2-MeTHF) at 78 °C
(Scheme 7).10 This resulted in the formation of a beige-green
slurry of the active catalyst. A solution containing a mixture of
11 and 12 (1.1 equiv) in 2-MeTHF was then added dropwise
over 2 h, and the reaction mixture was stirred at 78 °C for
18-24 h. Although these reaction conditions were effective on
small scale employing a stir-bar, mechanical stirring of the
reaction mixture resulted in increased reaction times. This
observation was attributed to a “grinding” effect of the
stir-bar.11,12 When the reaction was scaled to >100 g, the
reaction required heating at 78 °C for 5 days to give complete
conversion of the starting material. There did not appear to be
any adverse affects after prolonged heating as the reaction
profile remained clean. In addition, the reaction appeared to be
insensitive to the presence of residual mercury present from
the previous steps. Upon completion of the reaction, the reaction
mixture was cooled to room temperature and filtered. At this
stage of the synthesis, removal of both Pd and Hg to acceptable
levels was actively investigated employing the absorbent
screening protocol previously described from these laborato-
ries.13 From the initial screen, the polystyrene-based resin MP-
TMT that contains trimercaptotriazine was found to exhibit the
highest selectivity in removal of both Pd and Hg.14 The filtrate
from the coupling reaction was treated with MP-TMT resin,
resulting in the reduction in the level of residual Pd to 37 ppm
and Hg to <3 ppm. The resin was filtered, and the product
was crystallized from IPAc/heptane to give 22 in 74% overall
yield. Removal of the Boc protecting group was accomplished
with 5 N HCl in IPA at 50 °C. No detectable amounts of iso-
propyl esters resulting from trans esterification of either the
starting material 22 or the product 23 were observed by either
HPLC or NMR of the crude reaction mixture. The product 23
began to crystallize from the reaction mixture during the course
of the reaction, and upon cooling to room temperature,
compound 23 was isolated in analytically pure form in 97%
isolated yield.
Amide Bond Formation and Completion of the Synthesis.
The end game preparation of compound 1 involved amide bond
formation between imidazole acid 7 and naphthyl piperazine
23 (Scheme 8). To eliminate chromatography and facilitate
isolation of ester intermediate 14, a one-pot amide formation,
ester hydrolysis, acidification protocol was investigated. Our
investigations were first focused on appropriate activation of 7
and subsequent reaction with HCl salt 23. It was rapidly
established that activation with 1,1′-carbonyldiimidazole (CDI)
(1 equiv) in DMAc at room temperature for 1 h furnished the
intermediate acyl imidazole quantitatively.15 It was reasoned
that the liberated imidazole would also serve as an effective
(10) For a leading reference on the use of anhydrous K3PO4 in palladium-
catalyzed amininations, see: Wolf, J. P.; Tomori, H.; Sadighi, J. P.;
Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(11) For a detailed discussion on the effect of partical size and rate increase
on palladium-catalyzed aminations, see: Meyers, C.; Maes, B. U. W.;
Loones, K. T. J.; Bal, G.; Lemie`re, G. L. F.; Dommisse, R. A. J. Org.
Chem. 2004, 69, 6010.
(13) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; Dasilva,
J.; Henderson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang,
T. Org. Process Res. DeV. 2005, 9, 198.
(14) MP-TMP is commercially available from Argonaut, Inc. and Biotage.
(15) For leading references using CDI for the preparation of amides on
scale, see: (a) Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S.
Org. Process Res. DeV. 1993, 7, 244. (b) Vaidyanathan, R.; Kalthod,
V. G.; Ngo, D. P.; Manley, J. M.; Lapekas, S. P. J. Org. Chem. 2004,
69, 2565.
(12) For other recent references on the importance of particle size for
successful scale-up, see: (a) Wilk, B. K.; Mwisiya, N.; Helom, J. L.
Org. Process Res. DeV. 2008, 12, 785. (b) Qafisheh, N.; Mukho-
padhyay, S.; Joshi, A. V.; Sasson, Y.; Chauh, G.-K.; Jaenicke, S. Ind.
Eng. Chem. Res. 2007, 46, 3016.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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Scheme 8
base for neutralizing the HCl salt of 23 and facilitate amide
bond formation. Treatment of the preformed acyl imidazole of
7 with 23 (1 equiv) at room temperature resulted in incomplete
conversion to intermediate 14. However, upon heating to 50
°C complete conversion to 14 was observed after 6 h.
Saponification of methyl ester 14 was accomplished by the
direct addition of 3.5 equiv of 5 N NaOH to the reaction mixture
and heating for 4 h at 50 °C. The exact amount of NaOH used
in the saponification was found to be crucial. When increased
amounts of NaOH were employed, hydrolysis of the amide
bond resulted leading to the formation of 7 and 23, and
decreased amounts of NaOH led to incomplete ester hydrolysis.
After cooling the reaction mixture to room temperature, the pH
of the reaction mixture was adjusted to 5 by the addition of 5
N H3PO4. During the pH adjustment, the desired product 1
crystallized from the reaction mixture and was isolated in
analytically pure form in 86% overall yield.
In conclusion, we have outlined a rapid and efficient
multihundred gram synthesis of the potent CCK1R agonist 1.
The streamlined, chromatography-free approach to 1 involved
key process improvements in the preparation of imidazole acid
7, a complete overhaul in the preparation of the naphthyl
piperazine fragment 23 including an improved synthesis of
bromoanhydride 16, and increased productivity in the end game
coupling. The longest linear sequence was 7 steps starting from
18 and provided 1 in 23% overall yield.
mmol) of m-phenetidine 2, and the solution was cooled to an
internal temperature of 0-3 °C. To the cooled solution was
added 414 mL (414 mmol) of 1 M NaHMDS in THF over 20
min, during which time the internal temperature increased to 8
°C. After 20 min of stirring at 3-5 °C, a solution of 45.4 g
(387 mmol) of p-tolunitrile 9 in 50 mL of THF was added to
the dark solution over a period of 20 min. The reaction mixture
was then allowed to warm to room temperature and was stirred
at this temperature for 1 h. The reaction mixture was then diluted
with 500 mL of water and 500 mL of MTBE, and the layers
were separated. The organic layer was washed with 500 mL of
water and was used in the next reaction without further
purification. HPLC assay indicated 93.3 g (98%) of N-(3-
ethoxyphenyl)-4-methylbenzamidine 4. An analytical sample
was obtained by chromatography on silica gel, giving 4 as a
colorless solid: mp 95-96 °C; 1H NMR (CDCl3, 400 MHz) δ
1.41 (t, 3H, J ) 7.0 Hz), 2.40 (s, 3H), 4.01 (q, 2H, J ) 7.0
Hz), 4.89 (br s, 2H), 6.54-6.62 (m, 3H), 7.23 (m, 3H), 7.73
(d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.8,
21.3, 63.2, 107.6, 109.5, 113.8, 126.6, 129.1, 130.1, 132.7,
140.7, 150.9, 154.1, 160.0. Anal. Calcd for C16H18N2O: C,
75.56; H, 7.13; N, 11.01. Found: C, 75.44; H, 6.99; N, 10.98.
The above MTBE solution containing 93.3 g (367 mmol)
of crude 4 was concentrated under reduced pressure, and the
solvent was switched to a final volume of 900 mL of
1,4-dioxane. To the resulting 1,4-dioxane solution of 4 were
added 95.4 g (440 mmol) of 90% technical grade ethyl
bromopyruvate 5 and 80.0 g (917 mmol) of sodium bicarbonate.
The mixture was heated to 95-97 °C for 2 h and allowed to
cool to room temperature. The reaction mixture was diluted
with 1 L of water and 1 L of MTBE, and the layers were
separated. The organic layer was washed with 500 mL of water
and concentrated under reduced pressure while solvent switch-
ing to THF and a final volume of 450 mL. To the THF solution
containing crude 6 were added 330 mL of MeOH and 330 mL
(660 mmol) of a 2 N solution of NaOH. The mixture was stirred
at room temperature for 2-3 h, and 330 mL of 2 N HCl was
added until a final pH ∼3.0-3.5 was obtained. To the solution
was added 800 mL of IPAc, and the layers were separated.
The organic layer was washed with 600 mL of water. The
Experimental Section
All reagents were purchased from commercial sources and
used as received. 1H and 13C NMR spectra were recorded on a
Bruker 400 spectrometer at 400 and 100 MHz, respectively,
with chemical shifts given in ppm relative to TMS at δ ) 0.
Reaction mixtures and products were analyzed by reverse phase
HPLC on a Hewlett-Packard 1100 instrument using a 4.6 ×
250 mm Symmetry Shield RP18 column. Solvent compositions
consisted of 0.1% H3PO4 and acetonitrile with a flow rate of
1.5 mL/min.
Preparation of 1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-
1H-imidazole-4-carboxylic Acid (7). To a 2-L flask 3-neck
flask was charged 150 mL of THF (150 mL) and 51.7 g (376
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solvent was removed under reduced pressure with feeding of
IPAc (constant volume of ∼1.2 L, ca. 2 L of IPAc needed) to
remove residual THF and MeOH. During the course of the
distillation the product began to crystallize. The slurry was
heated to 70 °C, and 800 mL of heptane was added over 1 h.
The slurry was allowed to cool to room temperature, stirred
for 2 h, and filtered. The wet cake was washed with 100 mL of
heptane, and the product was dried in a vacuum oven at 40 °C
for 8 h under a stream of nitrogen to give 91 g (75% overall
resulting slurry was warmed to 60 °C. A separate 1-L
round-bottomed flask was charged with 189 g of solid
yellow HgO, 600 mL of water, and 200 mL of AcOH,
and the mixture was warmed to ∼ 50 °C to give a
homogeneous, colorless solution. The freshly prepared
mercury acetate solution was then added to the slurry of
16 in NaOH, and the reaction mixture was heated to
96-98 °C for 36-48 h. To the reaction mixture was then
added 800 mL of concentrated HCl, and the mixture heated
to 96-98 °C for 5 h, cooled to room temperature, and
aged overnight at room temperature. The resulting solid
was filtered, and the wet cake was slurry washed with
water (3 × 1 L) and then dried under vacuum/N2 sweep
to give 211 g of crude bromo acids 17:18 as a 1:3 mixture
of regioisomers.16 NOTE: The product at this point was
contaminated with ∼5500-8500 ppm Hg, and appropriate
precautions should be taken to aVoid exposure.
In a 5-L round-bottomed flask were added 440 g of
crude mixture of bromoacids 17:18 and 3.5 L of AcOH,
and the slurry was heated to reflux to give a homogeneous
solution. The solution was allowed to slowly cool to 65
°C, seeded with 1.00 g of pure 18, allowed to slowly cool
to room temperature, and aged overnight. The product was
then collected by filtration, washed with heptane, and dried
under vacuum/N2 sweep at 50 °C for 24 h to give 268 g
(92 wt %, 56%) of the desired regioisomeric product 18
as a colorless solid which was identical in all regards to
that published in the literature.7b NOTE: The product at
this point was contaminated with ∼1200 ppm Hg, and
appropriate precautions should be taken to aVoid expo-
sure.
Preparation of Methyl 3-Bromonaphthoate (11). A 5-L
3-neck flask equipped with a thermocouple and reflux
condenser was charged with 251.08 g (0.982 mol) of
bromoacid 18, 1.85 L of MeOH, and 26.2 mL (0.49 mol)
of concentrated H2SO4. The resulting slurry was heated
to 60-65 °C for 18 h until complete consumption of 18
was observed by HPLC. The reaction mixture was cooled
to room temperature and diluted with 1.0 L of 1:1 EtOAc/
hexane and with 1.0 L of water. The layers were well
mixed for 30 min and allowed to settle, and the bottom
aqueous layer was separated. The organic layer was
washed with 650 mL of brine and then treated with 259 g
of Darco G60 for 1 h. The mixture was filtered through
Solka Floc, rinsing the pad with 500 mL of 1:1 EtOAc/
hexane and then 500 mL of EtOAc. The solvent was
removed under reduced pressure, and the crude product
was dried under vacuum/N2 sweep to give 232.68 g of
bromo ester 11 (99 wt %, 89%) as a colorless solid which
was identical in all regards to that published in the
literature.7b
1
yield from 2) of 7 as a colorless solid: mp 162-163 °C; H
NMR (CDCl3, 400 MHz) δ 1.37 (t, 3H, J ) 7.0 Hz), 2.32 (s,
3H), 3.96 (q, 2H, J ) 7.0 Hz), 6.76 (m, 2H), 6.95 (dd, 1H, J
) 8.4 and 1.8 Hz), 7.08 (d, 2H, J ) 8.0 Hz), 7.30 (m, 3H),
7.88 (s, 1H), 10.12 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ
14.6, 21.4, 64.0, 112.0, 115.5, 117.9, 125.8, 128.8, 128.9, 129.1,
130.5, 132.3, 138.5, 139.6, 147.9, 159.8, 165.7. Anal. Calcd
for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.66;
H, 5.36; N, 8.51.
Preparation of 3-Bromonaphthallic Anhydride (16). A
50-L round-bottomed flask equipped with a mechanical stirrer,
a thermocouple, and a nitrogen inlet was charged with 5.11 kg
(25 mol) of naphthalic anhydride 15 and 25 L of 95-98%
sulfuric acid (25 L) at 20 °C. The mixture was stirred at 20-25
°C for 30 min to obtain complete dissolution and was cooled
to -5 to -10 °C. To the solution was added portion-wise 3.93
kg (13.8 mol) of dibromodimethylhydantoin over 1 h while
maintaining the internal reaction temperature was maintained
between -10 to -5 °C, and the mixture was stirred at this
temperature for 1 h and allowed to warm slowly to room
temperature overnight.
In a separate 100-L round-bottomed flask equipped with a
mechanical stirrer and thermocouple was added 50 L of water,
and the solution was cooled in an ice-water bath. The above
reaction mixture was added to the water with stirring over 1 h
while maintaining the internal temperature below 75 °C. The
resulting slurry was cooled to 30 °C and filtered. The reaction
flask was rinsed with 10 L of water, and the cake was washed
with 25 L of water and 25 L of 10% water in DMF. The wet
cake was dried under nitrogen/vacuum overnight.
The crude wet cake was transferred to a 100-L round-
bottomed flask equipped with a mechanical stirrer, nitro-
gen inlet, and addition funnel. To the crude product was
added 50 L of DMF, and the slurry was warmed to 90 °C
to give a homogeneous solution. The solution was allowed
to cool to 70 °C and seeded with 1.00 g of pure 16. The
slurry was allowed to cool to room temperature overnight.
To the slurry was added 5 L of water over 30 min, and
the slurry was aged for 1 h and filtered. The wet cake
was washed with 10 L of 10% water in DMF and then
with 10 L of MeOH. The crude product was dried under
a nitrogen flow for 3 h and then in vacuo at 70 °C
overnight to give 5.10 kg (95 wt %, 70% yield from 15)
as a colorless solid which was identical in all regards to
that published in the literature.7b
Preparation of tert-Butyl 4-[4-(Methoxycarbonyl)-2-
naphthyl]-1-piperazinecarboxylate (6). Two 140 g batches
were set up side-by-side and conducted in the same
manner. A 5-L 4-neck round-bottomed flask equipped with
a mechanical stirrer, thermocouple, 250 mL addition
Preparation of 3-Bromonaphthalic Acid (18). In a 5-L
3-neck round-bottomed flask equipped with a thermo-
couple and reflux condenser was charged 250 g of bromo
anhydride 16 and 2.0 L of 1 N NaOH solution. The
(16) Analysis of the crude product was carried out by HPLC as described
in ref 7b.
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1207

funnel, and a nitrogen inlet was charged with 1.4 L of
2-Me-THF, and the solvent was degassed for ∼2 min with
a submerged nitrogen line. To the solvent was added
sequentially 6.3 g (16.0 mmol) of ligand 21,17 7.60 g (13.0
mmol) of Pd(dba)2, and 336 g (1.58 mol) of powdered
K3PO4,18 and the system was evacuated under vacuum and
then purged with nitrogen. The resulting red slurry was
heated to 78 °C over ∼30 min, at which point the color
of the slurry changed to beige/light green.
In a separate 2-L round-bottomed flask was added 1.1
L of 2-Me-THF, and the solution was degassed for ∼2
min. To the solution were added 140.0 g (0.528 mol) of
ester 11 and 108.0 g (0.581 mol) of N-Boc-piperazine 12
followed by evacuation of the vessel under vacuum and
purging with nitrogen, and the mixture was stirred for ∼10
min at room temperature to fully dissolve the solids. The
mixture was then transferred via cannula to the 250-mL
addition funnel and was charged into the above mixture
containing the catalyst/ligand in 125 mL portions over a
2 h period while maintaining the internal reaction tem-
perature at 78 °C. The reaction mixture was aged at 78
°C for 5 days until full conversion was observed by HPLC.
Upon completion, the dark greenish brown slurry was
cooled to room temperature, and the solids were filtered
through a pad of Solka Floc, slurry rinsing the pad with
2-Me-THF. The dark orange brown filtrate was stirred with
MP-TMT resin10 (140 g) at room temperature for 1 h under
nitrogen. The solids were filtered, rinsing with 2-Me-THF,
and then held overnight at ambient temperature.
In a separate 5-L 4-neck round-bottomed flask equipped with
a mechanical stirrer, thermometer probe, short path distillation
head, and a vacuum line was transferred the above crude
reaction mixture via in-line filtration (5 µm pore size). The
solvent was removed under reduced pressure to a volume of ∼
980 mL while maintaining the internal temperature below 65
°C. The solvent was then switched to IPAc by concentration
under reduced pressure, flushing with ∼ 3 L of IPAc, and the
volume was adjusted to a final volume of 1.1 L. The resulting
slurry was then heated to an internal temperature of 70 °C to
dissolve solids, allowed to slowly cool over 1 h to 50 °C, and
then aged for 1 h at 50 °C, during which time the product began
to crystallize. To the slurry was added dropwise 3.5 L of heptane
over a 1 h period, and the slurry was stirred overnight at room
temperature. The slurry was filtered, and the wet cake was
washed with 500 mL of heptane. After drying for 3 h on the
filter pot under vacuum/N2 sweep, the solid was further dried
in a vacuum oven at 30 °C under a flow of nitrogen for 36 h to
give 280.0 g (97 wt %, 74%) of 22 as a yellow solid: mp
107-108 °C; 1H NMR (CDCl3, 400 MHz) δ 1.51 (s, 9H), 3.28
(m, 4H), 3.64 (m, 4H), 3.96 (s, 3H), 7.29 (d, 1H, J ) 2.6 Hz),
7.44 (m, 2H), 7.72 (m, 1H), 7.98 (d, 1H, J ) 2.6 Hz), 8.72 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 28.3, 43.1, 49.4, 52.1,
79.7, 115.9, 123.8, 125.2, 125.5, 126.4, 126.6, 127.3, 128.0,
135.1, 147.5, 154.6, 167.8. Anal. Calcd for C21H26N2O4: C,
68.09; H, 7.07; N, 7.56. Found: C, 68.13; H, 7.23; N, 7.56.
Preparation of 4-[4-(Methoxycarbonyl)-2-naphthyl]-1-
piperazine Hydrochloride 23. To a 5-L round-bottomed flask
equipped with a mechanical stirrer and thermocouple were
charged 1.5 L of IPA and 250 g (0.675 mol) of 22. To the
resulting slurry was added 675 mL of a 5 N hydrochloric acid
solution in IPA. The homogeneous solution was heated to 50
°C for 2 h, at which point the HCl salt of 23 began to crystallize
from solution. The slurry was cooled to room temperature and
filtered, and the wet cake was washed with 500 mL of IPA.
The wet cake was dried in a vacuum oven at 50 °C under a
stream of nitrogen for 24 h to give 211 g (95 wt %, 97% yield)
of 23 as a white solid: mp 242-243 °C; 1H NMR (CDCl3, 400
MHz) δ 3.23 (m, 4H), 3.52 (m, 4H), 3.92 (s, 3H), 7.42 (m,
1H), 7.48 9m, 1H), 7.55 (m, 1H), 7.84 (m, 1H), 7.93 (m, 1H),
8.50 (m, 1H), 8.73 (br s, 1H), 9.71 (br s, 1H); 13C NMR (CDCl3,
100 MHz) δ 42.7, 45.9, 52.7, 115.7, 122.9, 125.2, 125.6, 125.7,
127.1, 128.0, 128.4, 135.1, 146.8, 167.6. Anal. Calcd for
C16H19ClN2O2: C, 62.64; H, 6.24; N, 9.13. Found: C, 63.00;
H, 6.32; N, 9.05.
Preparation of 3-{4-[1-(3-Ethoxyphenyl)-2-p-tolyl-1H-
imidazole-4-carbonyl]-piperazin-1-yl}-naphthalene-1-car-
boxylic Acid (1). In a 5-L round-bottomed flask equipped with
a mechanical stirrer and thermocouple were charged 2.25 L of
DMAc and 225.7 g (0.70 mol) of imidazole acid 7. To the
solution was added 113.5 g (0.70 mol) of CDI in one portion.
The resulting mixture was aged at room temperature for 1 h,
and 214.8 g (0.70 mol) of 23 was added as a solid in one
portion. The resulting slurry was heated to 50 °C for 6 h. To
the reaction mixture was then added 490 mL (2.45 mol) of 5
N NaOH, and the solution was stirred at 50 °C for 4 h. The
reaction mixture was allowed to cool to room temperature and
was neutralized to pH ∼5 by the addition of 410 mL (2.05
mol) of 5 M aqueous phosphoric acid over 1 h. To the resulting
thick slurry was added 450 mL of water, and the slurry was
stirred for 2 h at room temperature and filtered. The wet cake
was washed with 1 L of water and was dried in a vacuum oven
at 55 °C under a stream of nitrogen for 48 h to give 340 g
(86%) of 1 as a light yellow solid: mp 230.1 (DSC); 1H NMR
(DMSO-d6, 400 MHz) δ 1.22 (t, 3H, J ) 7.0 Hz), 2.24 (s, 3H),
3.33 (m, 4H), 3.65-3.95 (br m, 2H), 3.95 (q, 2H, J ) 7.0 Hz),
4.21-4.55 (br m, 2H), 6.78 (dd, 1H, J ) 7.7 and 1.4 Hz), 6.91
(t, 1H, J ) 2.0 Hz), 6.95 (dd, 1H, J ) 8.3 and 2.0 Hz), 7.09 (d,
2H, J ) 8.1 Hz), 7.22 (d, 2H, J ) 8.1 Hz), 7.27-7.35 (m,
2H), 7.38-7.43 (m, 2H), 7.76 (d, 1H, J ) 8.3 Hz), 7.88 (s,
1H), 7.94 (d, 1H, J ) 2.4 Hz), 8.60 (d, 1H, J ) 8.3 Hz), 13.2
(br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 14.9, 21.3, 49.4,
63.9, 112.6, 114.8, 115.5, 118.5, 122.8, 124.9, 125.8, 125.9,
126.9, 127.4, 128.7, 128.8, 129.4, 130.8, 135.5, 136.9, 138.9,
139.0, 145.5, 147.8, 159.6, 162.2, 169.3. Anal. Calcd for
C34H32N4O4: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.79; H,
5.71; N, 10.01.
(17) Ligand 21 was purchased from Strem Chemicals, Inc. and was used
as received.
(18) Commercially available anhydrous powdered K3PO4 from Riedel de
Haen was employed.
Received for review July 28, 2008.
OP800176E
1208
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