Efficient large-scale synthesis of a 2,4,5-triarylimidazoline MDM2 antagonist

Article abstract of DOI:10.1021/op300294g

An improved, kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist is reported. The nicotinic acid component was prepared in three steps from ethyl 2-dimethylaminomethylene-3-oxo-butyrate. The coupling of the nicotinic acid with the meso-diamine selectively produced the monoamide which was cyclized in the presence of p-TSA/pyridine to give the imidazoline core. Phosgenation using bis(trichloromethyl) carbonate provided the key carbamoyl chloride intermediate, which was coupled with the side-chain amine, followed by chiral resolution with (R)-camphorsulfonic acid to give the final API.

Full text of DOI:10.1021/op300294g

Article
pubs.acs.org/OPRD
Efficient Large-Scale Synthesis of a 2,4,5-Triarylimidazoline MDM2
Antagonist
Lianhe Shu,* Chen Gu, Yan Dong, and Robert Brinkman
Process Research and Synthesis, Pharma Research and Early Development (pRED), Hoffmann-La Roche, Inc., 340 Kingsland Street,
Nutley, New Jersey 07110, United States
ABSTRACT: An improved, kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist is reported. The nicotinic acid
component was prepared in three steps from ethyl 2-dimethylaminomethylene-3-oxo-butyrate. The coupling of the nicotinic acid
with the meso-diamine selectively produced the monoamide which was cyclized in the presence of p-TSA/pyridine to give the
imidazoline core. Phosgenation using bis(trichloromethyl) carbonate provided the key carbamoyl chloride intermediate, which
was coupled with the side-chain amine, followed by chiral resolution with (R)-camphorsulfonic acid to give the final API.
camphorsulfonic acid, produced the desired enantiomer 2 in
36−41% yield and >99% ee.
INTRODUCTION
■
Tumor suppressor p53 is a potent transcription factor that
protects cells from malignant transformations.1 In many human
malignancies, MDM2 is overexpressed and effectively impairs
p53 functions.2 Inhibition of MDM2 would reactivate the p53
pathway, thus providing a potential cancer therapy.3 Since the
Synthesis of 7-Na. The synthesis of 4 was originally
reported by McCombie et al.,6 in which a THF solution of 3
and pivaloyl chloride was added simultaneously to a solution of
LiHMDS at −70 °C within 1−2 min to give 4 in moderate
yield after chromatography. Since the reaction is highly
exothermic, it can only be carried out on small scale (a few
grams of 3). In order to control the exotherm, 3 was initially
added to a solution of LiHMDS at −70 °C, and then pivaloyl
chloride was added dropwise. While the exotherm was well
controlled, a new byproduct 14 at various levels (up to 25%)
was detected by NMR analysis. This was also obtained by
adding LiHMDS to a solution of 3 at −78 °C. A plausible
mechanism for the formation of 14 is shown in Scheme 3.7
In order to minimize the dimerization of 3, the addition
order was reversed, and pivaloyl chloride was replaced by
trimethylacetic anhydride, which could coexist with LiHMDS at
low temperature. Compound 3 was thus added dropwise to a
premixed solution of LiHMDS and trimethylacetic anhydride at
∼−70 °C. The enolate generated from 3 was immediately
trapped by trimethylacetic anhydride. The reaction cleanly gave
4, with only 0.6% of 14 detected by HPLC analysis.
discovery of the Nutlin series of compounds (e.g., 1),4
a
number of MDM2 antagonists,5 including imidazoline 2, have
been identified and evaluated in preclinical/clinical studies.
In the original medicinal chemistry synthesis shown in
Scheme 1,5c 2 was prepared in 10 steps from commercially
available 3. This process is not suitable for large-scale
production due to several reasons: (1) at least five steps
required chromatography, including supercritical fluid chroma-
tography (SFC) on a chiral column for the separation of rac-12;
(2) the conversion of 3 to 4 was highly exothermic, with no
method of control; (3) the cyclization of 10 using POCl3 gave
11 in only 10% yield along with a large amount of a byproduct;
and (4) handling of a phosgene solution is dangerous on a large
scale. Therefore, a safe and efficient synthesis is required.
Herein, we describe an improved synthesis of 2, which has been
scaled up to the multikilogram scale.
Compound 5 was previously prepared from 4 by reaction
with ammonium acetate in ethanol at 95 °C.5c It can also be
prepared in one pot according to the published procedure.6
The isolation of 4 was therefore skipped, and the reaction
mixture was quenched with acetic acid (3 equiv). Ammonium
acetate thus generated from LiHMDS and acetic acid was found
sufficient for the conversion of 4 to 5. After the reaction stirred
at 60 °C for 30 min, HPLC analysis indicated clean conversion
of 4 to 5. Upon aqueous workup, 5 crystallized and was isolated
in 68−82% yield and >99% purity as an off-white solid. The
moderate yield was due to the loss of product in the aqueous
layer, as 5 has reasonable solubility in water. This process was
subsequently transferred to a contract supplier, thus no further
optimization was conducted in house.8
RESULTS AND DISCUSSION
■
An efficient synthesis of 2 has been developed that is
summarized in Scheme 2. The nicotinic acid component was
obtained in two steps and 67−80% yield from 3 as a sodium
salt, 7-Na. The monoacylation of diamine 9 with 7 cleanly gave
10, which was cyclized and phosgenated to give rac-12. The
coupling of rac-12 with 13, followed by resolution with (R)-
Received: October 19, 2012
© XXXX American Chemical Society
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a
The alkylation of 5 with ethyl iodide was carried out at 60 °C
in DMF using potassium carbonate as the base. After extractive
workup, 6 was obtained as a solution in methyl tert-butyl ether
(MTBE). Hydrolysis of 6 was initially performed in aqueous
ethanol using sodium hydroxide. However, the isolation of 7
was problematic due to its aqueous solubility. Direct
crystallization from the aqueous reaction mixture gave 7 in
only moderate yield, contaminated with various levels of
sodium chloride. Thus, the hydrolysis was carried out using a
minimal amount of water, and the product was isolated as the
corresponding sodium salt 7-Na in ≥99% purity and 98% yield
from 5.
Scheme 1. Original synthesis of 2
Synthesis of 11-TSA. We have previously reported a boric
acid-catalyzed direct condensation of meso-bis(4-chlorophenyl)-
ethane-1,2-diamine with a benzoic acid, which gave a cis-4,5-
bis(aryl)imidazoline in good yield.9 The presence of the two
methyl groups in 9 significantly impacts the reactivity of 9, and
no reaction was observed when a mixture of 9, 7 and boric acid
in xylenes was heated to reflux. A stepwise approach via 10 was
therefore considered.
The monoacylation of 9 was carried out under typical amide
preparation conditions using EDC·HCl as the coupling reagent.
After a mixture of 7-Na, diamine 9, a catalytic amount of HOBt
or its monohydrate, DIPEA, and EDC·HCl in MeTHF were
stirred at room temperature overnight, HPLC analysis indicated
a clean conversion to monoamide 10, which was obtained in
nearly quantitative yield after an aqueous wash and
crystallization from MeTHF−n-heptane. LC−MS analysis
indicated the presence of bis-amide 17 in the reaction mixture
at a level of 0.89%, but it purged well in the workup and was
not observed in isolated 10.
Cyclization of 10 in the presence of phosphorus oxychloride
under the original conditions5c,10 gave 11 in only 10% yield
after chromatography. The major product from this reaction
was 18 (Scheme 4). When phosphorus pentoxide was used as
the dehydration agent, de-ethylation occurred exclusively to
a
Reagents and conditions: a) t-BuCOCl, LiHMDS, THF, chromatog-
raphy, 63%; b) NH4OAc, EtOH, H2O, 76%; c) EtI, K2CO3, DMF,
80%; d) KOH, EtOH, yield not reported; e) SOCl2, yield not
reported; f) TEA, THF, chromatography, 85%; g) POCl3, toluene,
chromatography, 10%; h) phosgene, toluene, yield not reported; i)
chiral SFC separation, yield not reported; j) TEA, THF, chromatog-
raphy, yield not reported.
Scheme 2. New synthesis of 2
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Scheme 3. Plausible mechanism for the formation of byproduct 14
decomposition of 11 to 18 was detected (Figure 2); the levels
of 11 and 18 remained essentially constant at 94% and 4%,
respectively, even after heating the mixture to reflux for an
additional 21 h. After cooling to room temperature, 11-TSA
was isolated in 97% yield and 95.8% purity (containing 2.6% of
18). Material of this quality can be directly used in the next
step. Interestingly, pyridine and p-TSA were found to be the
ideal combination. Reactions catalyzed by p-TSA alone or with
2,6-lutidine in place of pyridine were observed to be slower and
generated higher levels (4.8−8.8%) of 18.
Preparation of rac-12. Due to the limited supply and
safety concerns regarding phosgene, alternative reagents, such
as p-nitrophenyl chloroformate,12 were tested. However, the
resulting intermediates did not react with amine 13.
Therefore, bis(trichloromethyl) carbonate (triphosgene), was
used to generate phosgene in situ. Triphosgene (0.37 equiv) in
CH2Cl2 was cooled to ≤5 °C and then treated with 0.1 equiv of
2,6-lutidine to give a solution of phosgene. Compound 11-HCl
was then added, followed by the dropwise addition of DIPEA.
The reaction was complete within 1 h. Excess phosgene was
quenched with water, and rac-12 was isolated in 89−92% yield
and >99% purity as a white solid after aqueous workup and
crystallization (Scheme 5).
As 11-TSA was prepared and isolated using the improved
cyclization conditions, it was decided to directly use this salt in
the phosgenation step following the procedure described above
for 11-HCl. The reaction, however, gave a lower conversion,
with a significant amount of p-toluenesulfonyl chloride detected
by HPLC analysis, indicating that p-TSA was also consuming
phosgene. Thus, a suspension of 11-TSA in CH2Cl2 was treated
with aqueous sodium carbonate to remove the p-TSA. The
resulting solution of 11 was then added to the in situ-generated
phosgene. After aqueous workup and dilution with n-heptane,
carbamoyl chloride rac-12 crystallized and was obtained as a
white solid in 86% yield and 98.5% purity. Based on molecular
weight data, the major impurity formed during the reaction was,
presumably, the cyclization product 19, generated from 18.
Although this impurity had good solubility and was removed
give 18 as the sole product in 68% yield. Subsequently, the
cyclization was found to proceed reasonably cleanly when 1-
propylphosphonic acid cyclic anhydride (T3P;11 1 equiv) was
used, and the reaction was stopped in 2 h. Product 11 was
obtained as a hydrochloride salt (11-HCl) in 90% yield and
≥96% purity (less than 2% of 18) after aqueous workup,
followed by salt formation with hydrogen chloride generated in
situ from methanol and trimethylchlorosilane. This process was
successfully scaled up to produce 1.5 kg of 11-HCl.
In order to test the robustness of this process, the reaction
was extended for an additional 20 h. While the cyclization was
complete within 2 h, the level of 18 increased almost linearly
with reaction time, reaching 50% after 22 h at the expense of
product 11, indicating that 18 was mainly generated from 11
(Figure 1a). Thus, it became critical that the reaction be
stopped at the right time point to minimize degradation, a
challenge at plant scale. As the de-ethylation is likely acid
catalyzed, base additives were considered to slow this process.
The addition of 2,6-lutidine (2 equiv) was found to significantly
retard the rate of the formation of 18 without a negative impact
on the cyclization rate (Figure 1b).
Subsequently, an improved cyclization procedure was
developed, using 1 equiv of p-toluenesulfonic acid (p-TSA)
buffered with 3 equiv of pyridine as the catalyst and a Dean−
Stark trap to remove water generated during the reaction. The
cyclization of 10 was complete within 3 h, and 11 precipitated
out from the reaction mixture as the p-TSA salt. More
importantly, once the reaction was complete, no further
Scheme 4. Cyclization of 10
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⧫
▲
Figure 2. Cyclization of 10 catalyzed by p-TSA and pyridine. 10,
11, 18.
■
In order to solve this issue, direct precipitation of rac-2 from
the reaction mixture was attempted. Thus, rac-12 was
suspended in CH2Cl2, and then 13-HCl was added followed
by addition of DIPEA. After stirring at room temperature
overnight, the reaction mixture became a thick slurry and
HPLC analysis indicated complete reaction. This slurry was
then diluted with water and n-heptane, worked up and filtered
to give the desired product in nearly quantitative yield. This
improved process was consistent in small scale test runs and
should be more reliable for large scale preparations.
After screening a variety of chiral acids, the resolution of 2
with (R)-camphorsulfonic acid (CSA) was the only hit
identified. In a solvent effect study,14 only THF and MTBE
gave a crystalline salt of 2-CSA with up to 20% enantiomer
enrichment. In THF, the diastereomeric purity of the salt was
significantly improved when only 0.5 equiv of camphorsulfonic
acid was used, and 2-CSA was obtained in 99.5% de and 36.5%
yield. In MTBE, however, the stoichiometry of camphorsulfonic
acid barely affected the chiral purity of the salt. On scale-up, a
solution of rac-2 in THF was treated with 0.5 equiv of (R)-CSA
at reflux for 1 h and stirred overnight. The resolved salt, 2-CSA,
was collected in 43% yield and 99.7% de.
The undesired enantiomer could be recovered from the
mother liquor by basic aqueous workup and crystallization. All
efforts to recycle the enantiomer to 11 by hydrolysis under
strong acidic or basic conditions were unsuccessful, as the
sterically hindered urea was very stable. Attempts to reduce the
urea moiety by treatment with lithium aluminum hydride in
toluene at reflux resulted in decomposition.
Figure 1. Cyclization of 10 catalyzed by T3P. (a) without an additive;
(b) with 2,6-lutidine (2.0 equiv) added; 10,
⧫
■
11, 18.
▲
during the crystallization, the loss of rac-12 in the filtrate
increased when 19 was present. Therefore, removing 18 from
11 prior to the phosgenation step is highly recommended for
further scale up.13
Though carbamoyl chloride 12 was compatible with weak
bases, such as aqueous sodium bicarbonate, it can be converted
back to 11 when treated with aqueous sodium hydroxide. This
provides an easy means for recycling the undesired enantiomer.
Therefore, a chiral resolution of rac-12 is highly desirable.
Unfortunately, crystallization screening with a variety of chiral
acids did not produce any fruitful results. The racemic form was
thus carried forward into the next step.
Preparation of Drug Substance 2. The coupling of rac-
12 with amine 13 was carried out in CH2Cl2 in the presence of
DIPEA. The reaction mixture was worked up, and after solvent
exchange to THF, the resulting suspension of rac-2 was directly
used in the resolution step. When this process was scaled up in
the pilot plant, phase separation during the aqueous workup
was found to be slow.
With the resolved salt 2-CSA in hand, the API was obtained
by neutralization with aqueous sodium carbonate in ethyl
acetate. The product 2 crystallized from ethyl acetate and n-
heptane, and was isolated in 98.7% chemical purity, 99.7% ee,
and 36.5% overall yield from rac-12.
CONCLUSION
In summary, we have developed an improved, multikilogram-
scale synthesis of 2 in seven steps and 20−27% overall yield
■
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Scheme 5. Preparation of rac-12 from 11-HCl
then iodoethane (12.5 mL, 155 mmol) was added. After stirring
at 60 °C overnight, the resulting suspension was diluted with
water (125 mL) and extracted with MTBE (200 mL). The
extract was washed with water (200 mL), concentrated to ∼100
mL, and diluted with ethanol (25 mL) and THF (200 mL).
Then, 50% sodium hydroxide (6.2 mL, 118 mmol) was added.
After stirring at 50 °C for 2 h, the mixture was cooled to room
temperature and diluted with MTBE (100 mL). The resulting
solid was collected by filtration, washed with MTBE (100 mL),
and dried to give 7-Na (27.0 g, 98% yield, 99% HPLC purity)
from 3. This process was successfully scaled up in a pilot plant
to produce >10 kg of API. While some optimization might be
required for a few minor issues, such as the low-temperature
reaction and the use of potentially hazardous HOBt, this
synthesis is considered adequate for the drug substance supply
at this stage. The recycling of the undesired enantiomer or
resolution of rac-12 would be the area for further development.
1
as a white solid; mp 303−304 °C; H NMR (400 MHz,
DMSO-d6) δ 8.27 (s, 1H), 6.82 (s, 1H), 4.10 (q, J = 7.0 Hz,
2H), 1.29 (t, J = 7.0 Hz, 3H), 1.28 (s, 9H); 13C NMR (100
MHz, DMSO-d6) δ 168.11, 168.02, 161.11, 148.28, 126.09,
102.83, 62.83, 37.10, 30.07, 14.18; HRMS calcd for
C12H17O3NNa [M + H] 246.1106, found 246.1103.
EXPERIMENTAL SECTION
■
rac-N-[(1R,2S)-2-Amino-1,2-bis(4-chlorophenyl)-1-
methylpropyl]-6-tert-butyl-4-ethoxynicotinamide (10).
Two flasks were each charged with 9 (1.20 kg, 3.88 mol), 7-
Na (1.06 kg, 4.32 mol),16 HOBt (97.3 g, 0.72 mol)
(CAUTION: HOBt can be explosive under certain conditions),
MeTHF (12 L), and DIPEA (622 g, 4.81 mol). The resulting
suspension was stirred for 10 min, and then EDC·HCl (870 g,
4.53 mol) was added to each flask in one portion. After stirring
overnight, the contents of the two flasks were combined,
diluted with MeTHF (12 L), and washed with water (3 × 7.2
L). The organic phase was then equally divided into two
portions, and each portion was concentrated to remove ∼12 L
of solvent. The residues were each diluted with n-heptane (4.8
L) and further concentrated to remove 4.8 L of solvent. The
residues were again each diluted with n-heptane (4.8 L), and
the resulting suspensions were stirred at 50 °C for 30 min and
at room temperature overnight. The contents of the two flasks
were combined and filtered. The filter cake was washed with n-
heptane (2 × 4.8 L) and dried to give 10 (3.99 kg, quantitative
yield, 96.2% HPLC purity) as a light-brown solid; mp 184−185
General. Achiral HPLC analyses were performed on an
Agilent Zorbax XDB-C8 (100 mm × 3 mm, 3.5 μm) column
with 30−100% CH3CN/H2O (+0.1% TFA) as mobile phase
over 15 min at flow rate of 0.5 mL/min. Chiral HPLC analysis
were performed on Chiralcel OD (250 mm × 4.6 mm, 5 μm)
column using EtOH/hexane (1:4) as mobile phase at flow rate
of 1 mL/min. Compound 9 was prepared in three steps and
54% yield from 1,2-bis(4-chlorophenyl)ethane-1,2-dione using
an optimized process based on a previously described route.5c
Bulk quantities of 7-Na were prepared by a CMO using a
process based on the procedures described below.
Ethyl 6-tert-Butyl-4-oxo-1,4-dihydropyridine-3-car-
boxylate (5). A solution of LiHMDS15 (1.6 M in THF, 210
mL, 336 mmol) was cooled to −50 °C, and then trimethyl-
acetic anhydride (30.0 g, 161 mmol) was added over 15 min at
≤−50 °C. The resulting mixture was further cooled to about
−75 °C. Then, 3 (30.1 g, 163 mmol) was added over 40 min at
≤−70 °C. After stirring for an additional 20 min, the mixture
was warmed to room temperature, and AcOH (30.0 mL, 500
mmol) was added over 5 min. The mixture was stirred at 60 °C
for 30 min and then concentrated under reduced pressure to
remove THF. The residual aqueous mixture was diluted with
EtOAc (240 mL) and water (90 mL). The organic phase was
separated, washed with sat. Na2CO3 (120 mL) and water (90
mL), concentrated to ∼100 mL, and diluted with n-heptane
(240 mL). The resulting suspension was further concentrated
to ∼220 mL, cooled to ∼5 °C, and stirred for 1 h. The solid
was collected by filtration, washed with cold n-heptane (50
mL), and dried by suction to give 5 (24.5 g, 68% yield, >99%
1
°C; H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.68 (s,
1H), 7.18 (d, J = 7.8 Hz, 2H), 7.14 (s, 1H), 7.11 (d, J = 8.8 Hz,
2H), 6.99 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 7.8 Hz, 2H), 4.47
(m, 2H), 2.19 (s, 2H), 1.86 (s, 3H), 1.59 (s, 3H), 1.58 (t, J =
7.0 Hz, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ
173.20, 162.57, 162.35, 151.20, 143.66, 140.99, 131.24, 130.73,
129.79, 129.12, 126.60, 126.48, 116.08, 103.02, 64.87, 63.74,
60.58, 37.68, 29.79, 24.69, 20.72, 14.65; HRMS calcd for
C28H34O2N3Cl2 [M + H] 514.2028, found 514.2019.
1
5-[(4S,5R)-4,5-Bis(4-chlorophenyl)-4,5-dimethyl-4,5-
dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxypyridine
p-Toluenesulfonic Acid Salt (11-TSA). Two flasks were each
charged with 10 (1.38 kg, 2.69 mol), p-TSA·H2O (538 g, 2.82
mol), pyridine (692 mL, 8.56 mol) and toluene (13.8 L). Each
reaction mixture was stirred at reflux for 4.5 h, and water was
removed via a Dean−Stark trap. After cooling to room
temperature, the contents of the two flasks were combined
and filtered. The filter cake was washed with MTBE (2 × 8 L)
HPLC purity) as an off-white solid. H NMR (400 MHz,
DMSO-d6) δ 8.27 (s, 1H), 6.82 (s, 1H), 4.10 (q, J = 7.1 Hz,
2H), 1.29 (t, J = 7.1 H, 3H), 1.28 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 181.53, 175.53, 169.35, 167.63, 150.75, 107.85,
61.61, 37.66, 29.59, 14.08; HRMS calcd for C12H18O3N [M +
H] 224.1287, found 224.1280.
Sodium 6-tert-Butyl-4-ethoxynicotinate (7-Na). A
mixture of 5 (25.0 g, 112 mmol), DMF (75 mL), and
K2CO3 (25.0 g, 181 mmol) was stirred at 60 °C for 30 min, and
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and dried to give 11-TSA (3.50 kg, 97% yield, 95.8% HPLC
purity) as a white solid; mp 303 °C dec; H NMR (500 MHz,
THF (3 × 2.4 L) and dried to give 2-CSA (1.70 kg, 43% yield,
98.5% chemical purity, and 99.7% de) as a white solid; mp
176−178 °C.
1
DMSO-d6) δ 10.96 (s, 2H), 8.86 (s, 1H), 7.46 (m, 2H), 7.31 (s,
1H), 7.20−7.16 (m, 4H), 7.11 (m, 2H), 7.10−7.06 (m, 4H),
4.42 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.95 (s, 6H), 1.45 (t, J =
7.0 Hz, 3H), 1.38 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ
176.66, 163.64, 160.06, 149.87, 145.61, 138.83, 137.60, 132.14,
128.11, 128.00, 127.64, 125.46, 106.26, 103.74, 72.64, 65.29,
38.30, 29.63, 22.67, 20.78, 14.02; HRMS calcd for
C28H32ON3Cl2 [M + H] 496.1922, found 496.1912.
rac-(4S,5R)-2-(6-tert-Butyl-4-ethoxypyridin-3-yl)-4,5-
bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimida-
zole-1-carbonyl Chloride (rac-12). Compound 11-TSA
(6.83 kg, 10.22 mol) was suspended in CH2Cl2 (34 L) and
toluene (19.5 L). The mixture was stirred at room temperature,
and a solution of Na2CO3 (1.13 kg) in water (11.3 L) was
added over 30 min. The resulting solution was stirred for 30
min. The organic layer was then separated, washed with water
(19.5 L), and concentrated under reduced pressure to remove
∼36 L of solvent. The residue was diluted with CH2Cl2 to 10 L
and equally divided into four portions.
Four flasks were each charged with triphosgene (285 g, 0.96
mol) and CH2Cl2 (8.5 L). The resulting solutions were cooled
to −7 °C. To each flask was added 2,6-lutidine (26 mL, 0.22
mol) over 15 min. Then, the solution of 11 (2.5 L each, 2.55
mol in theory) in CH2Cl2 from above was added over 45 min,
followed by the addition of DIPEA (597 mL, 3.43 mol). The
resulting four reaction mixtures were stirred below 0 °C for 2.5
h and at room temperature overnight and then were quenched
with water (5 L each). The contents of the four flasks were
combined and washed with water (2 × 20 L). The organic
phase (∼60 L) was concentrated to remove ∼25.6 L of solvent
and then was diluted with n-heptane (31.2 L). The resulting
solution was further concentrated to remove an additional 22 L
of solvent. The suspension was filtered, and the collected solid
was washed with n-heptane (2 × 6.8 L) and dried to give rac-12
(4.92 kg, 86% yield, 98.4% HPLC purity) as a white solid; mp
202−204 °C; 1H NMR (400 MHz, acetone-d6) δ 8.65 (s, 1H),
7.25−7.00 (m, 9H), 4.53 (m, 1H), 4.31 (m, 1H), 2.23 (s, 3H),
1.79 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.41 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 174.72, 163.09, 154.36, 150.23, 144.56,
139.55, 133.08, 127.91, 127.78, 127.65, 114.35, 101.89, 64.45,
38.09, 30.05, 24.66, 21.65, 14.50; HRMS calcd for
C29H31O2N3Cl3 [M + H] for 558.1482, found 558.1474.
2-{1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxypyridin-3-yl)-4,5-
bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimida-
zole-1-carbonyl]piperidin-4-yl}acetamide (R)-Camphor-
sulfonic Acid Salt (2-CSA). Two flasks were each charged
with rac-12 (1.23 kg, 2.20 mol), CH2Cl2 (12 L), DIPEA (1.93
L, 11.08 mol), and 13-HCl (492 g, 2.75 mol). After stirring
overnight, the reaction mixtures were combined and diluted
with water (20 L). The organic layer was separated, washed
with 0.4 M HCl (20 L), diluted with additional CH2Cl2 (20 L),
and washed with water (20 L). After concentrating essentially
to dryness, the residue was suspended in THF (5 L) and
reconcentrated to near dryness. This operation was repeated
one more time, and the resulting wet solid rac-2 was divided
equally into three portions. To each portion was added THF
(11 L), and the resulting mixtures were warmed to 50−55 °C
to give clear solutions. Then, (R)-CSA (148 g each, 0.64 mol)
was added, and the mixtures were heated to reflux for 1.5 h and
at room temperature overnight. The contents of three flasks
were combined and filtered. The filter cake was washed with
2-{1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxypyridin-3-yl)-4,5-
bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimida-
zole-1-carbonyl]piperidin-4-yl}acetamide (2). Compound
2-CSA (3.00 kg, 3.34 mol) was charged portionwise to an
extractor containing a mixture of EtOAc (39 L) and Na2CO3
(975 g, 9.20 mol) in water (19.5 L). The suspension was stirred
for 2 h, and then the layers were separated. The organic phase
was washed with water (2 × 19.5 L) and then filtered through a
pad of Celite (200 g). The pad was washed with EtOAc (2 × 3
L), and the combined filtrate and washes were concentrated
while n-heptane (39 L) was added. The resulting suspension
was further concentrated to ∼21 L, then filtered. The filter cake
was washed with n-heptane (2 × 3 L) and dried to give 2 (1.88
kg, 85% yield, 98.7% chemical purity and 99.7% ee) as a white
17
1
solid; mp 206−209 °C; H NMR (400 MHz, DMSO-d6)
δ
8.65 (s, 0.4H), 8.64 (s, 0.6H), 7.23−6.90 (m, 10H), 6.73 (s,
0.4H), 6.68 (s, 0.6H), 4.33 (m, 1H), 4.05 (m, 1H), 3.57 (m,
0.4H), 3.50 (m, 0.6H), 3.42−3.25 (m, 1H), 2.66 (m, 0.6H),
2.52 (m, 0.6H), 2.21 (m, 0.4H), 1.99 (m, 0.4H), 1.90 (s, 1.2H),
1.88 (s, 1.8H), 1.72−1.18 (m, 20H), 0.99 (m, 0.4H), 0.88 (m,
0.4H), 0.27 (m, 0.6H), −0.58 (m, 0.6H); 13C NMR (100 MHz,
DMSO-d6) δ 173.06, 172.43, 172.22, 162.94, 162.44, 155.08,
154.93, 153.02, 149.79, 141.40, 140.72, 140.64, 130.59, 130.15,
128.23, 128.14, 126.66, 126.14, 113.72, 102.01, 101.59, 76.38,
76.25, 74.93, 64.09, 47.45, 45.07, 41.81, 40.91, 37.63, 32.17,
31.97, 31.56, 30.61, 30.45, 30.07, 29.86, 29.70, 23.71, 20.09,
19.85, 13.82, 13.73; HRMS calcd for C36H44Cl2N5O3 [M + H]
664.2816, found 664.2818.
rac-5-[(4S,5R)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-
4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-1H-pyridin-4-
one (18). Compound 10 (500 mg, 0.97 mmol) was dissolved
in toluene (10 mL), then P2O5 (138.0 mg, 0.97 mmol) was
added. The mixture was stirred at reflux overnight, then cooled
to room temperature and quenched with water, followed by 2
M sodium hydroxide (2.9 mL, 5.8 mmol). The organic phase
was separated, washed with water (2 × 10 mL), and
concentrated. The resulting foam was crystallized from
MTBE−n-heptane (1:2, v/v, 15 mL) to give 18 (310 mg,
68% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-
d6) δ 8.71 (s, 1H), 7.09 (d, J = 8.7 Hz, 4H), 6.97 (d, J = 8.7 Hz,
4H), 6.42 (s, 1H), 3.50 (br, 1H), 3.39 (s, 1H), 1.77 (s, 6H),
1.24 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 174.48,
163.13, 149.19, 141.45, 131.12, 127.99, 127.26, 111.09, 71.82,
62.77, 36.58, 29.57, 23.14; HRMS calcd for C26H28ON3Cl2 [M
+ H] 468.1609, found 468.1600.
18
4-Hydroxyisophthalic Acid Diethyl Ester (14):
1H
NMR (400 MHz, CDCl3) δ 11.31 (s, 1H), 8.57 (d, J = 2.5 Hz,
1H), 8.12 (dd, J = 9.0, 2.5 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H),
4.45 (q, J = 7.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.45 (t, J =
7.2 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.79, 165.61, 165.11, 136.45, 132.38, 121.69,
117.67, 112.37, 61.91, 60.98, 14.35, 14.18.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lshu@verizon.net
Notes
The authors declare no competing financial interest.
F
dx.doi.org/10.1021/op300294g | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(18) Compound 14 was isolated from 4 by flash column
chromatography on silica gel.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Masami Okabe for helpful discussion and
Ms. Rui Yu and Bojana Nedjic for analytical support. We thank
Dr. Hanspeter Michel of Formulation Research Department for
HRMS analysis.
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(17) NMR showed a 2:3 mixture of rotamers of 2.
G
dx.doi.org/10.1021/op300294g | Org. Process Res. Dev. XXXX, XXX, XXX−XXX