A practical synthesis of a cis -4,5-Bis(4-chlorophenyl)imidazoline Intermediate for Nutlin analogues

Article abstract of DOI:10.1021/op300254q

A practical synthesis of cis-4,5-bis(4-chlorophenyl)imidazoline, a key intermediate for Nutlin analogues, is reported. The title compound was prepared in 81-88% yield by boric acid catalyzed direct condensation of meso-bis(4-chlorophenyl)ethane-1,2-diamine with a benzoic acid. The process was successfully scaled up in a pilot plant, resulting in >15 kg of the product.

Full text of DOI:10.1021/op300254q

Technical Note
pubs.acs.org/OPRD
A Practical Synthesis of a cis-4,5-Bis(4-chlorophenyl)imidazoline
Intermediate for Nutlin Analogues
Lianhe Shu,* Ping Wang, Wen Liu, and Chen Gu
Process Research and Synthesis, Pharma Research and Early Development (pRED), Hoffmann-La Roche, Inc., 340 Kingsland Street,
Nutley, New Jersey 07110, United States
ABSTRACT: A practical synthesis of cis-4,5-bis(4-chlorophenyl)imidazoline, a key intermediate for Nutlin analogues, is
reported. The title compound was prepared in 81−88% yield by boric acid catalyzed direct condensation of meso-bis(4-
chlorophenyl)ethane-1,2-diamine with a benzoic acid. The process was successfully scaled up in a pilot plant, resulting in >15 kg
of the product.
such as EtAlCl2 and MeAlCl2, were unsuccessful, a two-step
process via the cyclization of monoamide 6 was pursued. As
shown in Scheme 2, treatment of acid 5 with 1,1′-carbon-
yldiimidazole (CDI) in THF, followed by the addition of
diamine 2, produced a mixture of the desired monoamide 6 and
bis-amide 7. The monoacylation of a diamine is challenging
since the resulting monoamide is usually more reactive than the
diamine.7 In order to improve the selectivity of 6, solvent and
concentration effects were investigated. Among the solvents
screened,8 THF gave the best selectivity. When the reaction
was run under high concentrations, compound 6 precipitated
from the reaction mixture, thus effectively minimizing the
formation of bis-amide 7. It has been reported that carbon
dioxide could catalyze the coupling of amines with
imidazolides,9 but the coupling of diamine 2 with the
imidazolide of 5 proceeded faster under CO2-free conditions
and gave better mono selectivity. The acylation was complete
within 16 h and gave 6 and 7 in a ratio of ca. 15−20:1. Crude 6
containing 5−9% of 7 was obtained in ca. 84% yield by
precipitation. The purity could not be upgraded by
crystallization as 7 is significantly less soluble than 6.
With compound 6 in hand, the cyclization (Scheme 3) was
examined in xylenes at reflux in the presence of a strong acid,
e.g., p-toluenesulfonic acid (p-TSA) or sulfuric acid. Water
generated from the reaction was removed via a Dean−Stark
trap. While reactions catalyzed by a catalytic or stoichiometric
amount of p-TSA did not go to completion, presumably due to
the formation of p-TSA anhydride, reactions with 1 equiv of
sulfuric acid in xylenes proceeded quite smoothly. After the
reaction mixture was stirred at reflux overnight, the sulfate of 4
was collected in 90−95% yield by filtration. The impurity 7
carried through from the previous step was removed as it
remained in the solution phase.
INTRODUCTION
■
Since their discovery in 2004, Nutlins (e.g., Nutlin-3, 1) have
received extensive attention due to their cancer treatment
potential.1,2 A variety of Nutlin analogues have been prepared
and evaluated in preclinical studies.3 A common component of
these compounds is a cis-4,5-diaryl-4,5-dihydro-1H-imidazole
core, such as 4. In the original synthesis (Scheme 1), this
imidazoline moiety was constructed via condensation of meso-
diamine 2 with benzoate 3 in the presence of a stoichiometric
amount of trimethylaluminum.3 Due to safety concerns
regarding the handling of pyrophoric alkylaluminum com-
pounds and the tedious workup caused by the alumina gel, this
direct condensation method is not suitable for large scale
production. A number of approaches for the synthesis of
imidazolines from 1,2-diamines have been reported in the
literature,4 but none appeared promising for scale-up. After the
completion of this investigation, two interesting papers
appeared: a novel asymmetric synthesis of Nutlin-3 using the
aza-Henry reaction5 and a catalytic desymmetrization of meso-
diamines.6 While the reactions gave encouraging enantiose-
lectivities and yields, both syntheses are not considered ready
for large scale preparation before those catalysts used become
readily available. Herein, we describe a convenient one-step
synthesis of 2-(4-tert-butyl-2-ethoxyphenyl)-cis-4,5-bis(4-chlor-
ophenyl)-4,5-dihydro-1H-imidazole (4), a key intermediate for
a number of Nutlin analogues.3 This process has been
successfully scaled up in a pilot plant.
The scale-up of this process, however, was not as smooth. As
shown in Table 1, whereas a 1 g scale reaction (entry 1) was
complete within 6 h using only 0.05 equiv of sulfuric acid, a 100
g scale reaction required 1 equiv of sulfuric acid and heating for
40 h (entry 3), though 4-H2SO4 was still obtained in good yield
RESULTS AND DISCUSSION
Because initial attempts to replace AlMe3 with catalytic
amounts of relatively less pyrophoric aluminum reagents,
■
Received: September 13, 2012
Published: October 19, 2012
© 2012 American Chemical Society
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Organic Process Research & Development
Technical Note
Scheme 1. Original Synthesis of 4
Scheme 2. Preparation of Monoamide 6
dehydration agent (i.e., thionyl chloride) gave either very low
conversion or significant decomposition. Fortunately, boric
acid, a cheap, nontoxic, and environmentally benign weak acid,
was found to be an effective catalyst. Boric acid was previously
reported to be a good catalyst for the formation of amides from
carboxylic acids and amines.10
Scheme 3. Cyclization of 6 to 4
When a mixture of 2, 5, and a catalytic amount of boric acid
in xylenes was heated to reflux, the reaction directly gave the
cyclized product 4 (Scheme 4), with only a trace amount of 6
detected in the reaction mixture. With 5−10 mol % of boric
acid, the reaction was complete after stirring at reflux overnight.
After dilution with dichloromethane11 and aqueous work-up,
the resulting solution of 4 was treated with conc HCl. Upon
azeotropic removal of water, the product, 4-HCl, crystallized
and was collected by filtration in 81−88% yield and >98%
purity. Unlike the two-step synthesis that did not scale up, this
direct condensation process performed consistently from
milligram to multikilogram at pilot plant scale. Besides 4, this
method has also been successfully utilized for the preparation of
the imidazoline core of Nutlin-3 (1) at the kilogram scale.
Table 1. Condensation of 6 at Different Scale
entry
scale (g)
H2SO4 (equiv)
time (h)
yield (%)
1
2
3
4
1.0
10
0.05
1.0
6
16
89
95
92
78
100
1.0
40
1300
1.0
100
and purity. At the 1.3 kg scale (entry 4), the reaction became
even slower and the prolonged heating caused significant
degradation, impacting the yield and quality of the product.
The reaction was stopped prematurely at 100 h, and the
product was obtained in only 78% yield.
The reason for the diminished reaction rate on scale-up is
not evident, but if it is assumed that the reaction occurs only at
the hot surface of the reaction vessel, which is at a higher
temperature than xylenes at reflux, the scale-up effect could
then be explained by a decrease in the surface area per reaction
volume.
CONCLUSION
■
In summary, we have developed a simple and convenient one-
step synthesis of 2-(4-tert-butyl-2-ethoxyphenyl)-cis-4,5-bis(4-
chlorophenyl)-4,5-dihydro-1H-imidazole using boric acid as the
catalyst. The robustness of this process was subsequently
demonstrated in a pilot plant.
EXPERIMENTAL SECTION
As the strong acid catalyzed process was deemed unsuitable
for further scale-up, the direct condensation of 2 and 5 was
investigated. Treatment of a mixture of 2 and 5 with strong
acids, such as sulfuric acid or p-toluenesulfonic acid, or
■
General. HPLC analysis was performed on Agilent Zorbax
XDB-C8 (100 mm × 3 mm, 3.5 μm) column with 5−100%
CH3CN/water (+0.1% TFA) over 10 min as mobile phase at a
Scheme 4. Boric Acid Catalyzed Condensation of 2 and 5 to Give 4
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Organic Process Research & Development
Technical Note
flow rate of 0.5 mL/min. Compound 2 was prepared in 51%
yield from p-chlorobenzaldehyde using an optimized process
based on a published route.12 Bulk quantity of compound 5 was
prepared by contract suppliers following the procedure
described below.
J = 7.0 Hz, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, DMSO-d6)
δ 165.44, 159.44, 157.26, 133.31, 119.48, 114.94, 109.63, 65.77,
35.41, 30.96, 14.66.
rac-N-[(1R,2S)-2-Amino-1,2-bis(4-chlorophenyl)ethyl]-
4-tert-butyl-2-ethoxybenzamide (6). A 500 mL three-
necked round bottomed flask equipped with a mechanic stirrer,
thermometer, and nitrogen inlet/outlet was charged with 5
(20.0 g, 90.0 mmol) and THF (40 mL). Then CDI (15.0 g,
92.3 mmol) was added portionwise over 10 min. After 30 min
of stirring, NMR analysis indicated the complete conversion to
imidazolide. The flask was evacuated under vacuum to remove
CO2, and then 2 (27.8 g, 99.0 mmol) was added. The solution
was stirred at room temperature overnight, and NMR analysis
indicated a complete reaction. The resulting thick suspension
was dissolved in THF (40 mL) and isopropyl acetate (120
mL). After being washed with water (2 × 80 mL), the organic
phase was concentrated under atmospheric pressure. Additional
isopropyl acetate (80 mL) was added to ensure that water was
removed azeotropically. After a total of ca. 200 mL of solvent
was removed, n-heptane (240 mL) was added slowly. The
resulting suspension was filtered. The filter cake was washed
with n-heptane (2 × 100 mL) and dried to give 6 (40.2 g,
containing 9 wt % of 7 as determined by NMR, 84% yield) as
2-Bromo-5-tert-butylphenol. A 500 mL 3-necked round
bottomed flask equipped with a magnetic stirrer, addition
funnel, thermometer, and nitrogen inlet/bubbler was charged
with 3-tert-butylphenol (48.0 g, 319 mmol) and dichloro-
methane (100 mL), and then a solution of bromine (16.5 mL,
320 mmol) in dichloromethane (50 mL) was added over 15
min, while maintaining the temperature of the reaction mixture
below 35 °C. After the addition was complete, NMR analysis
indicated a complete reaction. The reaction was then quenched
with a solution of NaHSO3 (1.0 g) in water (150 mL). After 5
min of stirring, the organic layer was separated, washed with
water (200 mL), and concentrated at 30 °C/20 mmHg to give
2-bromo-5-tert-butylphenol13,14 (72.5 g, 99% yield) as a
colorless oil, which was used directly in the next step.
1-Bromo-2-ethoxy-4-tert-butylbenzene. A 500 mL
three-neck round bottomed flask equipped with a magnetic
stirrer, additional funnel, condenser, and nitrogen inlet/bubbler
was charged with 2-bromo-5-tert-butylphenol (20.0 g, 87.3
mmol) and THF (200 mL). Then, potassium tert-butoxide
(10.3 g, 91.7 mmol) was added with stirring. To the resulting
yellow solution was added iodoethane (7.4 mL, 92.6 mmol).
The mixture was heated to reflux for 3 h, additional iodoethane
(1.0 mL, 12.6 mmol) was added, and heating was continued for
an additional 5 h. TLC analysis indicated complete reaction.
After cooling to room temperature, the reaction mixture was
diluted with n-heptane (50 mL), washed with water (2 × 50
mL) and saturated sodium chloride solution (50 mL), and
concentrated at 30 °C/20 mmHg to give 1-bromo-2-ethoxy-4-
tert-butylbenzene15 (21.8 g, 97% yield) as a colorless oil, which
was directly used in the next step.
1
off-white solid. H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =
8.3 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H),
7.30 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.10 (d, J =
8.5 Hz, 2H), 7.08 (d, J = 1.5 Hz, 1H), 7.02 (dd, J = 8.2, 1.5 Hz,
1H), 5.21 (dd, J = 8.3, 5.8 Hz, 1H), 4.26 (d, J = 5.8 Hz, 1H),
4.23 (q, J = 7.1 Hz, 2H), 1.92 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H),
1.28 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 163.64,
156.26, 155.86, 142.33, 138.86, 131.42, 131.26, 130.51, 129.45,
128.97, 127.68, 127.66, 119.45, 117.48, 109.97, 64.31, 58.41,
58.23, 34.84, 30.84, 14.58; HRMS calcd for C27H31Cl2N2O2 [M
+ 1] 485.1763, found 485.1757.
4-tert-Butyl-2-ethoxy-benzoic Acid (5). A 500 mL three-
necked round bottomed flask equipped with a mechanic stirrer,
condenser, thermometer, and nitrogen inlet/outlet was charged
with magnesium (2.16 g, 88.8 mmol) and THF (160 mL), and
1-bromo-2-ethoxy-4-tert-butylbenzene (2.0 g, 7.8 mmol) was
added, followed by a few crystals of iodine. Upon heating to 40
°C, the reaction initiated, and then additional 1-bromo-2-
ethoxy-4-tert-butylbenzene (18.0 g, 70.0 mmol) was added
dropwise at a rate to maintain a gentle reflux. The resulting
mixture was heated to reflux with stirring for 2.5 h. NMR
analysis indicated complete reaction. The reaction mixture was
cooled to −20 °C with a dry ice−acetone bath, then carbon
dioxide was bubbled into the reaction mixture until the
absorption of gas was complete. TLC analysis indicated
complete reaction. The mixture was allowed to warm to
room temperature and was stirred overnight. Then 1 M HCl
(160 mL, 160 mmol) was added, and the mixture was extracted
with ethyl acetate (160 mL). The organic layer was washed
with saturated sodium chloride solution (160 mL), dried over
magnesium sulfate, and concentrated under reduced pressure to
give 17.0 g of crude 5 as an orange solid. This material was
redissolved in n-heptane (120 mL) at reflux. After cooling to 0
°C and stirring at this temperature for 20 min, the resulting
solid was collected by filtration, washed with cold n-heptane
(20 mL), and dried by suction to give 5 (14.80 g, 85.6% yield)
2-(4-tert-Butyl-2-ethoxyphenyl)-cis-4,5-bis(4-chloro-
phenyl)-4,5-dihydro-1H-imidazole hydrochloride (4-
HCl). A mixture of 2 (10.40 kg, 36.98 mol), 5 (8.70 kg,
39.13 mol), and boric acid (228.3 g, 3.69 mol) in xylenes (71.6
kg) was agitated at 145−148 °C for 24 h while a total of 41 L of
solvent was removed by distillation via a Dean−Stark trap. The
reaction mixture was cooled to room temperature, diluted with
dichloromethane (150 kg), washed with 7.5 wt % aqueous
sodium bicarbonate (53.9 kg), and water (2 × 52 L), and then
concentrated at atmospheric pressure. The residue was diluted
with toluene (112 kg), and an additional 10 L of solvent was
removed. Concentrated hydrochloric acid (4.1 kg, 49.87 mol)
was added, and a further 63 L of solvent was then removed by
distillation at atmospheric pressure. The batch was cooled to
room temperature and dropped to a filter dryer with the aid of
toluene (8.7 kg). The collected solids were washed with toluene
(26.0 kg) and dried to give 4-HCl (15.1 kg, 81% yield, HPLC
1
purity 98.64%) as a white solid. Mp 227−228 °C; H NMR
(400 MHz, DMSO-d6) δ 10.92 (s, 2H), 7.98 (d, J = 8.1 Hz,
1H), 7.27 (dd, J = 7.4, 1.6 Hz, 1H), 7.26−7.22 (m, 5H), 7.12
(m, 4H), 5.98 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0
Hz, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ
163.58, 160.17, 157.65, 134.12, 132.47, 130.69, 129.32, 127.94,
117.89, 110.28, 108.98, 64.57, 63.42, 35.47, 30.62, 14.24;
HRMS calcd for C27H29Cl2N2O [M + 1] 467.1657, found
467.1652.
1
as an off-white solid. H NMR (300 MHz, DMSO-d6) δ 10.90
(brs, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.15 (dd, J = 8.3, 1.5 Hz,
1H), 7.03 (d, J = 1.5 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.57 (t,
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Organic Process Research & Development
Technical Note
AUTHOR INFORMATION
Corresponding Author
lshu@verizon.net
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Hanspeter Michel of Formulation Research
Department for HRMS analysis.
■
REFERENCES
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1
(15) H NMR spectrum of the crude product is in agreement with
the structure.
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