An efficient synthesis of a multipotent eicosanoid pathway modulator

Article abstract of DOI:10.1021/op800257u

An efficient, scalable synthesis of the multipotent eicosanoid pathway modulator 2-[3-[3[[5-ethyl-4'-fluoro-2-hydroxyl[1,1'-bi-phenyl]4-yl]oxy]- propoxy]2-propoxylphenoxy]benzoic acid (1) is described. The process consists of nine chemical steps with the

Full text of DOI:10.1021/op800257u

Organic Process Research & Development 2009, 13, 268–275
An Efficient Synthesis of a Multipotent Eicosanoid Pathway Modulator†
Matthew H. Yates,* Thomas M. Koenig, Neil J. Kallman, Christopher P. Ley, and David Mitchell
Eli Lilly and Company, Chemical Product Research and DeVelopment DiVision, Indianapolis, Indiana 46285, U.S.A
Scheme 1. Retrosynthesis of compound 1
Abstract:
An efficient, scalable synthesis of the multipotent eicosanoid
pathway modulator 2-[3-[3[[5-ethyl-4′-fluoro-2-hydroxyl[1,1′-bi-
phenyl]-4-yl]oxy]-propoxy]2-propoxylphenoxy]benzoic acid (1) is
described. The process consists of nine chemical steps with the
longest linear sequence having six isolations. Palladium metal-
mediated cross-coupling assembles the biaryl fragment, and
selective SNAr chemistry is used to construct the resorcinol
fragment. The synthesis converges at a phenolic coupling
with an alkyl chloride to give the core structure of the active
pharmaceutical ingredient (API). Further elaborations of
the core and salt formation provides the final API. This
process produced the drug candidate in 41% overall yield
at multikilogram scale.
A convergent strategy from the first-generation synthesis for
compound 1 is outlined retrosynthetically in Scheme 1. Since
the synthesis was intended to prepare bulk drug substance
material, pivotal intermediates 2 and 3 required preparation from
readily available starting materials. Therefore, a major challenge
posed by this approach was establishing regiocontrol of each
aryl substitution pattern. A Suzuki-Miyaura cross-coupling of
a fluoro aryl boronic acid and a substituted resorcinol ether
provided biphenyl 2. Diaryl ether 3 was derived from coupling
of propyl resorcinol and a suitable 2-halogenated benzonitrile.
Coupling of the two pivotal intermediates followed by deben-
zylation and hydrolysis provided compound 1.
The synthesis of fragment 2 is shown in Scheme 2.
Commercially and readily available 2′,4′-dihydroxyacetophe-
none was selectively benzylated to provide 5 in >85% yield.5
The resulting phenol was O-alkylated in quantitative yield with
1,3-bromochloropropane using sodium hydride as the base in
THF.
Introduction
Studies on the role of eicosanoids in tumor cell growth led
to the examination of multipotent eicosanoid pathway modulator
(MEPM), 2-[3-[3[[5-ethyl-4′-fluoro-2-hydroxyl[1,1′-biphenyl]-
4-yl]oxy]-propoxy]2-propoxylphenoxy]benzoic acid (1), as an
anticancer agent.1 The compound has shown antiproliferative
activity against a number of tumor cell lines at low micromolar
concentrations, which are expected to be clinically attainable.
As a single agent, the compound is active against BxPC3
xenograft tumors in mice, and it has been shown to enhance
gemcitabine activity in vitro.2 Compound 1 in combination with
gemcitabine also showed increased activity over either com-
pound alone. These results generated significant interest in
clinically testing compound 1 both as a single agent and in
combination therapy with gemcitabine.
Scheme 2. Preparation of biphenyl 2
Results and Discussion
First-Generation Synthesis. The first-generation synthesis
was an efficient and practical multikilogram synthesis derived
from the development of three methodologies: a robust
Suzuki-Miyaura cross-coupling,3 a ketone reduction, and an
interesting biaryl ether formation. The development of these
methodologies provided a practical, convergent synthesis of
compound 1 to deliver early-stage material requirements.4
† This paper is dedicated to the memory of our friend and former colleague
Dr. Christopher R. Schmid.
* Author to whom correspondence may be sent. E-Mail: yatesmh@lilly.com.
(1) Ding, X. Z.; Talamonti, M. S.; Bell, R. H., Jr.; Adrian, T. E. Anti-
Cancer Drugs 2005, 16, 467.
Attempts at using various methods for ketone reduction to
the hydrocarbon derivative gave poor yields for our purpose.
For example, ionic hydrogenation6 with triethylsilane and
(2) Hennig, R.; Ding, X. Z.; Tong, W.; Witt, R. C.; Jovanovic, B. D.;
Adrian, T. E. Cancer Lett. 2004, 210, 41.
(3) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419.
(4) Sawyer, J. S.; Bach, N. J.; Baker, S. R.; Baldwin, R. F.; Borromeo,
P. S.; Cockerham, S. L.; Fleisch, J. H.; Floreancig, P.; Froelich, L. L.
J. Med. Chem. 1995, 38, 4411.
(5) Hatayama, K.; Yokomori, S.; Kawashima, Y.; Saziki, R.; Kyogoku,
K. Chem. Pharm. Bull. 1985, 33, 1327.
(6) (a) Olah, G. A.; Wang, Q.; Prakash, G. K. S. Synlett 1992, 8, 647. (b)
Olah, G. A.; Arvanaghi, M.; Ohannesian, L. Synthesis 1986, 9, 770.
268
•
Vol. 13, No. 2, 2009 / Organic Process Research & Development
10.1021/op800257u CCC: $40.75
2009 American Chemical Society
Published on Web 01/22/2009

trifluoroacetic acid gave <60% yield. On a large scale, the major
problem encountered was product isolation from silane byprod-
uct. Variations in this methodology such as using other proton
donor-proton acceptor pairs or addition of fluoride sources5
during workup did not enhance isolated yields. In view of the
poor yields from ionic hydrogenation, we examined an alternate
synthesis method. Reduction of 2-benzoylresorcinol and 2-n-
propionylresorcinol to the alkylresorcinol has been reported with
sodium borohydride after prior acylation with ethyl chlorofor-
mate in 55% and 22% yield, respectively.7 In this manner, 5
was reacted with methyl chloroformate and triethylamine in
THF to form the methyl carbonate. Addition of a solution of
sodium borohydride followed by acidic workup provided the
desired ethyl derivative 6 in 78% yield. This method of
reduction was developed for a 300-gal scale.8 The sodium
alkoxide of 6 was reacted with 1,3-bromochloropropane to
provide 7. While initial studies used NaH to form the alkoxide,
sodium tert-butoxide was preferred when the reaction was
scaled up. Bromination of 7 with NBS along with the
Suzuki-Miyaura cross coupling between 8 and 4-fluorophenyl
boronic acid proceeded without incident to provide 2 in 90%
yield.
Ullmann reaction conditions9 were explored for preparing biaryl
ether 3 (Scheme 3). Reaction of 2-propyl resorcinol and 2-iodom-
ethylbenzoate with copper in THF provided the biaryl ether 9 in
32% yield. This low yield was largely due to product isolation
and purification of the resulting noncrystalline product. Since large
quantities of 3 were required, we turned our attention to other means
of preparation. We envisioned that nucleophilic aromatic substitu-
tion of 2-fluorobenzonitrile with 2-propyl resorcinol would provide
an appropriate synthon. In this approach (Scheme 3), the nitrile
moiety would play the dual role of activation for nucleophilic
aromatic substitution and provide the carboxylic acid equivalent
upon hydrolysis. Several conditions were developed for this
transformation. In every case, more than 2 equiv of base was
required for successful reaction. The optimum conditions developed
used 2 equiv of solid sodium hydroxide in DMSO as solvent to
provide 3 in 70% yield.
remained intact at 55-60 psi of hydrogen, with 10% palladium
on carbon at 10-15 °C in ethanol for 10 h. Hydrolysis of 12 with
12.5 M sodium hydroxide in methanol provided compound 1 in
almost quantitative yield.
Scheme 4. First-generation synthesis of API 1
Although the first-generation synthesis of compound 1
provided multikilogram quantities in nine steps, control of
reaction-critical process parameters was absent. This lack of
detail for each step precluded complete impurity control.
Therefore, process development of each step was investigated
in order to understand each reaction sequence along with its
impact on impurity control. Our process development focused
on the following areas: (a) sodium borohydride/formate-
mediated reduction of 2-hydroxyacetophenones, (b) the
Suzuki-Miyaura cross-coupling, (c) selective SNAr biaryl ether
formation, (d) coupling of fragments 2 and 3, and (e) further
elucidation to the API.
Sodium Borohydride/Formate Reduction and Alkylation.
Analysis of early lots of API found unacceptable levels (>0.1%)
of impurities that originated from these first few steps of the
synthesis. The main process impurities from this sequence were
the styrene impurity 19, the dimer 20, and the bis-alkylated
compound 21. All three impurities were persistent throughout
the rest of the synthesis and were difficult to remove during
processing. The styrene and dimer compounds are formed
during the quinone methide reduction as depicted in Sch-
eme 5.
Scheme 3. Synthesis of the biaryl ether
Scheme 5. Mechanism of reduction and impurity
generation
Coupling of 2 and 3 with sodium hydroxide in DMSO furnished
11 in 91% yield (Scheme 4). To increase solubility upon nitrile
hydrolysis, the phenol functionality of 11 was first deprotected
using hydrogenolysis conditions. In several cases, concomitant
reduction of the nitrile group was observed. Switching to hydrogen
transfer methods using palladium on carbon as catalyst and
ammonium formate gave the desired phenol 12 in 90% yield on
small scale. However, due to concerns about the sublimation of
ammonium carbonate and defluorination, this reaction was not
implemented on pilot-plant scale.10 Therefore, we decided to
reinvestigate the hydrogenolysis conditions and found that the nitrile
(7) Stealey, M. A.; Shone, R. L.; Miyano, M. Synth. Commun. 1990, 20,
1869.
(8) Mitchell, D.; Doecke, C. W.; Hay, L. A.; Koenig, T. M.; Wirth, D. D.
Tetrahedron Lett. 1995, 36, 5335.
Vol. 13, No. 2, 2009 / Organic Process Research & Development
•
269

These impurities react in subsequent transformations and
form additional impurities as well. Fortunately, the reduction
impurities can be controlled by maintaining the addition rate
to ensure sufficient borohydride is available for reaction. The
bis-alkylated impurity 21 was routinely seen at ∼3-5% levels
during the alkylation reaction but could be controlled to <1%
with careful crystallization of 7. The control of 21 at this stage
was important because, despite the fact that it is symmetrical,
the reaction rates differed for the subsequent electrophilic
bromination and Suzuki cross-coupling steps. As depicted in
Scheme 6, if R1 * R2, this can give rise to a mixture of dimer
impurities which proved difficult to reject downstream.
significant conversion (∼15%) to the desired product, supporting
other observations that these types of reactions are quasi-
heterogeneous.12 Very low levels of aryl halide homocoupling
(<0.5%) was observed which could be further reduced with
proper degassing. The choice of Pd/C catalyst was not crucial
in this reaction (Figure 1). We found that either standard or
Scheme 6. Formation of dimer impurity 21
Figure 1. Screen of different Pd/C catalysts.
eggshell dispersion catalysts were effective. Oddly, a higher
Pd loading on the catalyst (10% vs 5%) did not increase the
rate significantly, which also supports the theory that the forward
reaction is due to a low level of dissolved Pd.
Several solvents were screened; the reaction worked well
in alcohols with more than two carbons, but organic cosolvents
such as toluene tended to slow the desired reaction (Figure 2).
Suzuki-Miyaura Cross-Coupling. The final step required
to complete the biaryl fragment was the Suzuki-Miyaura cross
coupling of 8 with 4-fluorophenylboronic acid. Initially, Pd(0)
was generated in situ from Pd(OAc)2 and triphenylphosphine.
This reaction was shown to be highly variable, depending on
trace impurities in the arylbromide. Reaction completion could
be achieved by adding more Pd(OAc)2 and PPh3, but control
of residual metal became difficult and varied from >1000 ppm
to ∼20 ppm in the isolated products (Scheme 7). Recent
communications have demonstrated the use of heterogeneous
catalysis to effect similar couplings.11 We found that Pd/C very
cleanly produced the desired compound and controlled the Pd
level to <20 ppm in the isolated biaryl fragment 2.
Scheme 7. Heterogeneous Pd coupling
Figure 2. Solvent effects on reaction completion (ave refers to
the average of all isomers).
For ease of isolation we chose a biphasic solution of tert-butanol
and 25% aq K2CO3 which allowed phase separation for removal
of residual boronic acid.
Selective SNAr Biaryl Ether Formation. The biaryl ether
was originally made via a SNAr reaction of 2-fluorobenzonitrile
and 2-propyl resorcinol with NaH in DMSO. For environmental
and safety reasons we were interested in exploring alternative
systems to assemble this fragment. First, we wanted to confirm
that these were the best fragments to bring together. Catalytic
Buchwald-Hartwig conditions and additional SNAr electro-
philes were compared for selectivity and yield, and none were
superior to 2-fluorobenzonitrile (Scheme 8).
The heterogeneous coupling worked well with a variety of
commercial hydrogenation catalysts in several solvents. Interest-
ingly, the coupling did not work in DMF with solid K2CO3.
Pretreatment of arylhalide 8 with Pd/C and filtration through a
0.45 µm filter before introduction of the boronic acid gave
(9) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389. (b) Ullmann,
F. Ber. Dtsch. Chem. Ges. 1904, 37, 853. (c) Jackson, W. T.; Froelich,
L. L.; Gapinski, D. M.; Mallett, B. E.; Sawyer, J. S. J. Med. Chem.
1993, 36, 1726. (d) Sawyer, S. J.; Baldwin, R. F.; Saussy, D. L.;
Froelich, L. L.; Jackson, W. T. Bioorg. Med. Chem. Lett. 1993, 3,
1985.
This SNAr reaction is a delicate balance between the
reactivity needed for the acceptor and the selectivity of the
bifunctional resorcinol to minimize impurity formation and
270
•
Vol. 13, No. 2, 2009 / Organic Process Research & Development

Scheme 8. Alternative assembly of the aryl ether fragment
Table 2. Screen of solvents in SNAr reaction
in situ
yield of
pdt 3
in situ
yield of
dimer
% dec
F-CN
anisole
THF
IPA
diglyme
DMI
DMF
NMP
9:1 NMP/DMSO
DMSO
0.2
0.4
1.1
0.1
0.2
0.2
0.3
11.7
4.4
8.5
9.5
3.1
0.6
1.2
56.2
1.4
7.2
2.2
6.0
3.5
9.6
7.5
57.3
73.3
77.8
81.7
94.8
but these conditions resulted in more hydrolysis of the 2-fluo-
robenzonitrile. Since this may affect throughput, a careful cost
analysis needs to be conducted before finalizing these condi-
tions.
maximize yield. We have identified several decomposition and/
or side reactions that occur during the coupling (Scheme 9).
Scheme 9. Impurity generation during SNAr reaction
A variety of bases and solvents were screened to take
advantage of a counterion effect to increase selectivity (Table
1). The significant difference in response factors necessitated
the use of in situ yield based on a standard curve to accurately
assess each reaction. Not surprisingly, when hydrates were used,
the 2-fluorobenzonitrile decomposed rapidly so that almost no
product was formed. The use of KOH resulted in more
decomposition of the 2-fluorobenzonitrile; however, the selec-
tivity for product over dimer was ∼10% higher, providing a
significant yield increase.
Figure 3. Fraction factorial for SNAr reaction.
Coupling of 2 and 3. The convergence at step 7 is an ether
formation to give the core structure of compound 1 (Scheme
10). This chemistry was also initially run in DMSO with NaH
as the base.
Scheme 10. Alkyl chloride coupling
Table 1. Screen of bases in SNAr reaction
in situ
yield of
product 3
in situ
yield of
dimer
% dec
F-CN
Mg(OH)2
0.6
1.2
0.2
0.3
0.1
2.0
11.0
8.6
0.0
94.5
89.8
0.8
1.7
10.5
9.6
Bu4NOH· 30 H2O
Me4NOH · 5 H2O
LiOH
NaOH
CsOH · H2O
KOH
12.6
35.3
79.9
86.3
94.8
97.5
3.1
2.5
KOH w/PTC
4.8
At least 2 equiv of base is required to reduce dimer
formation. With the use of 3 equiv of KOH, several solvents
were screened for improved stability or selectivity (Table 2).
NMP/DMSO was the only comparable result and was not likely
to surpass pure DMSO.
Alkoxide bases and additional mixed toluene solvent systems
were also tested and gave very high levels of dimer and inferior
conversion. The data confirmed that KOH in DMSO are the
preferred reaction conditions.13 A fractional factorial was run
to find optimal temperature, base equivalents, and reaction
volumes (Figure 3). The reaction space that gave the highest
yield was more dilute, with more base, at a lower temperature,
For environmental and safety concerns we needed to verify
that these conditions were appropriate and address impurity
control in this step. Hydrolysis of the nitrile, as seen in Step 6,
is still a liability in this step (Scheme 11). The alkyl chloride
of the biaryl fragment is also labile to hydrolysis or elimination.
These process impurities were seen as high as 0.7% and 6.1%,
respectively, under these conditions.
Alternative conditions of solvent, base, and temperature were
screened. It was found that MeCN might be a suitable substitute
for DMSO, but with it there is an additional liability of solvent
hydrolysis giving acetamide, which is a known carcinogen.14
There was no significant difference in the use of solid or
Vol. 13, No. 2, 2009 / Organic Process Research & Development
•
271

Figure 4. Impurity rejection and control at coupled product 9.
Scheme 11. Impurity formation from alkyl chloride
Scheme 12. Preferred deprotection order
concentrated aqueous base solutions, but there was a 6%
increase in yield for NaOH vs KOH. Alkoxide bases favored
elimination to give the olefin 18 in a number of solvents and
excess base led to the hydrolysis of the nitrile. Due to the
nonpolar nature of the product, the isolation/purification was
developed out of DMSO/methanol which effectively purges
most of the impurities (Figure 4).
Scheme 13. Defluorination during hydrogenolysis
Further Elucidation to the API. The original process
removed the benzyl protecting group by transfer hydrogenation
and then hydrolyzed the nitrile. Due to the potential for oxidation
of the free phenol and the harsh conditions needed to hydrolyze
the nitrile, it was desirable to evaluate conversion to the acid
and then benzyl protecting group removal (Scheme 12).
Amide hydrolysis was very straightforward in EtOH/NaOH
with no side reactions or new impurities formed. During the
hydrogenolysis of the benzyl group, the main impurity cor-
responded to defluorination (Scheme 13). This impurity was
not eliminated during the isolation of 11 or subsequent salt
formation.
The desfluoro impurity was seen sporadically from 0.04%
to 5.14% when transfer hydrogenation was used. Initially, it
was thought that catalyst type was responsible for its presence,
but further experimentation revealed the same variability with
a number of commercial catalysts. A likely explanation is
variability in the amount of reducing agent available for the
desired reaction which may lead to “hydrogen-starved” condi-
tions allowing oxidative insertion of the palladium.15 While
pressure hydrogenolysis (∼50 psi) limits what equipment can
be used, in this case it significantly reduced the level of
defluorination. A screen of commercially available catalysts (5%
Pd/C 50% wet) in several solvent combinations gave conditions
that successfully eliminated the formation of 23.
Conclusions
A robust synthesis of compound 1 has been developed. The
synthetic robustness is attributable to improvements made in
272
•
Vol. 13, No. 2, 2009 / Organic Process Research & Development

Scheme 14. Final synthesis
the aryl ketone reduction, cross coupling, and aryl ether-forming
transformations. The ketone reduction offers a strategy that
circumvents a problematic purification requirement. In the cross-
coupling, simplified catalyst systems that are readily available
may be utilized. A SNAr reaction was adopted for preparing
the biaryl ether moiety.
In addition to the synthetic sequence each reaction parameter
was examined to determine byproduct(s) formation. This
investigation contributed to an overall impurity-control strategy
along with addressing potential safety parameters. The above
development resulted in a modified and improved process which
provides compound 1 with six isolations in a 41% overall yield
from 4 (Scheme 14).
369.7 mol), and acetone (300 L) was stirred at 40-45 °C for
45 min. Benzyl bromide (50.6 kg, 295.8 mol) was added to
the slurry and the resulting mixture stirred at 40-45 °C for
5 h. Progress of the reaction was monitored by HPLC (such as
4.6 × 25 cm Zorbax Rx-C8, acetonitrile/0.01 N sulfuric acid,
75/25 as eluent system; 1.0 mL/min). After being cooled to
room temperature, 2 N hydrochloric acid was slowly added until
the pH was 7.0-7.5. The mixture was cooled to 0 °C and then
filtered. The resulting product cake was washed with water (149
L), isopropyl alcohol (225 L), and finally with heptane (225 L)
to provide 58.6 kg (84%) of compound 5, mp 101-103 °C. IR
(CHCl3) 3705, 3590, 2975, 1631, 1579, 1507, 1371, 1253, 1135,
1067 cm-1; 1H NMR (CDCl3, 300 MHz) δ 12.74 (s, 1 H), 7.62
(d, J )9.49 Hz, 1 H), 7.25-7.46 (m, 5 H), 6.54-6.50 (m, 3
H), 5.09 (s, 2 H), 2.57 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 202.6, 165.2, 135.9, 132.4, 128.7, 128.3, 127.5, 114.1, 108.1,
101.9, 70.2, 26.2; mass spectrum m/z (relative intensity) 242
(M+, 100). Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found:
C, 74.77; H, 5.34.
1-Bromo-2-(phenylmethoxy)-4-[(3-chloropropyl)oxy]-5-
ethylbenzene (8). Ethyl chloroformate (53.3 kg, 491 mol) was
added to a solution of THF (91 kg), triethylamine (50 kg, 500
mol), and compound 5 (91.0 kg, 375.6 mol) at 20-25 °C.
Progress of the reaction was monitored by HPLC (such as 4.6
× 25 cm Zorbax Rx-C8, acetonitrile/ 0.01 N sulfuric acid, 65/
35 as eluent system; 1.0 mL/min). The reaction mixture was
stirred for 1 h at 20-25 °C before quenching with water (220
L). The organic portion was separated and added to a basic
solution of NaBH4 (30 kg, 793 mol); two additional portions
of NaBH4 were added (20 kg in 70 kg of water and 10 kg in
60 kg of DI water). These solutions were added to achieve
Experimental Section
All reagents were obtained from commercial suppliers and
used without further purification. Solvents, including tetrahy-
drofuran, tert-butylmethyl ether (MTBE), and dimethoxymethane,
were used without drying or further purification. Melting points
were obtained on a Thomas-Hoover capillary melting point
1
apparatus and are uncorrected. H and 13C NMR data were
obtained on a QE-300 instrument. Elemental analyses were
provided by the Physical Chemistry Department of the Lilly
Research Laboratories. Due to the timing of the project, not all
of the optimized procedures were scaled up to pilot scale; thus,
the procedures below represent the largest-scale demonstration
of these procedures.
4-Benzyloxy-2-hydroxyacetophenone (5). A slurry of
compound 4 (45 kg, 295.8 mol), potassium carbonate (51.1 kg,
(10) Defluorination is discussed later in this paper, and there are safety
concerns with ammonium carbonate plugging condensers upon scale
up. For more information see: Slade, J.; Parker, D. J.; Girgis, M.;
Mueller, M.; Vivelo, J.; Liu, H.; Bajwa, J. S.; Chen, G. P.; Carosi, J.;
Lee, P.; Chaudhary, A.; Wambser, D.; Prasad, K.; Bracken, K.; Dean,
K.; Boehnke, H.; Repicj, O.; Blacklock, T. J. Org. Process Res. DeV.
2006, 10, 78.
(13) Although in Table 1 KOH with PTC gave slightly better results, it
was not felt that the added complexity was worth the slight improve-
ment in yield, especially since most of the yield loss was due to
hydrolysis and not dimerization.
(14) Acetamide is listed by IARC as a Level IIb compound: “There is
sufficient evidence in experimental animals for the carcinogenicity of
acetamide.” IARC Monographs on the EValuation of Carcinogenic
Risks to Humans; International Agency for Research on Cancer: Lyon,
France, 1999; Vol. 71, pp 1211-1221.
(15) Similar phenomena have been noted by other groups; see: Brands,
K. M. J.; Krska, S. W.; Rosner, T.; Conrad, K.; Corley, E. G.; Kaba,
M.; Larsen, R. D.; Reamer, R. A.; Sun, Y.; Tsay, F.-R. Org. Process
Res. DeV. 2006, 10, 109–117.
(11) First example: Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett.
1994, 35, 3277. For a recent review see: Yin, L.; Liebscher, J. Chem.
ReV. 2007, 107, 133.
(12) For an excellent discussion of the nature of these reactions see: Davies,
I. W.; Matty, L.; David, L.; Hughes, D. L.; Reider, P. J. J. Am. Chem.
Soc., 2001, 123, 10139. Conlon, D. A.; Pipik, B.; Ferdinand, S.;
LeBlond, C. R.; Sowa, J. R., Jr.; Izzo, B.; Collins, P. C.; Ho, G. J.;
Williams, J. M.; Shi, Y. J.; Sun, Y. AdV. Synth. Catal. 2003, 345,
931.
Vol. 13, No. 2, 2009 / Organic Process Research & Development
•
273

reaction completion. The biphasic solution was filtered and the
aqueous layer discarded. To the organic layer was added
1-bromo-3-chloropropane (148 kg, 940 mol) and solid potas-
sium hydroxide (33 kg, 825 mol). The mixture was heated at
reflux for 3 h and reaction completion confirmed. The reaction
mixture was cooled to <25 °C and phosphoric acid was added
to adjust the pH to 6.5-7.5 before cooling to 0 °C. N-
Bromosuccinimide (1.15 equiv) was added in portions while
maintaining the temperature at less than 15 °C. After bromi-
nation was complete (as determined by HPLC), the mixture
was treated with solid sodium sulfite until a negative starch/
iodide test was obtained. At ambient temperature the slurry was
filtered to remove insoluble salts, and the lower aqueous layer
was separated. The organic layer was concentrated at atmo-
spheric pressure until constant temperature reached 85 °C.
Methanol was added, and additional distillate was removed.
After more methanol was added, the solution was cooled to
30-35 °C and seeded, then cooled to 0-5 °C, filtered,and
rinsed before drying overnight in vacuo at 35 °C. The yield
was 36.6 kg (78%) of compound 8, mp 55-57 °C. IR (CHCl3)
2969, 2934, 2876, 1602, 1575, 1500, 1468, 1398, 1282, 1251,
1163, 1081, 1060, 1028, 887 cm-1. 1H NMR (CDCl3, 300 MHz)
δ 7.55-7.28 (m, 7 H), 5.13 (s, 2 H), 4.03 (t, J ) 5.78 Hz, 2
H), 3.73 (t, J ) 6.30 Hz, 2 H), 2.54 (q, J ) 7.55 Hz, 2 H), 2.20
(qn, J ) 6.0 Hz, 2 H), 1.15 (t, J ) 7.25 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 156.3, 153.7, 136.7, 132.7, 128.60, 128.0,
127.2, 102.9, 100, 71.5, 64.6, 41.5, 32.2, 22.4, 14.2; mass
spectrum m/z (relative intensity) 384, 382 (M+, 100); Anal.
Calcd for C18H20BrClO2: C, 56.34; H, 5.25; Br, 20.82; Cl,
9.24; O, 8.34. Found: C, 56.62; H, 5.31; Br, 20.60; Cl, 9.03.
5-Fluorophenyl-4-benzyloxy-2-(3-chloropropyloxy)ethyl-
benzene (2). Compound 8 (53.1 g, 138.4 mmol), tert-butanol
(5 vol), 4-fluorobenzeneboronic acid (20 g, 143 mmol), and aq
25% (w/w) K2CO3 (5 vol) were added to a reaction vessel. The
resulting solution was degassed and heated to 80 °C before
introduction of Pd/C as an aqueous slurry. The mixture was
heated for 3 h and sampled for reaction completion (<99.5%
conversion). Toluene (1 vol) was added and the mixture filtered
to remove catalyst. The lower aqueous phase was separated and
the organic layer washed with 25% K2CO3 (5 vol). The organic
layer was concentrated to remove 3.5 vol before adding back
methanol (3.5 vol). Distillation was continued at reduced
pressure at 40-45 °C. After solvent exchange to MeOH was
completed, the solution was cooled to 20 °C, and 3.5 vol of
water was added and held for 1 h. The solid was filtered and
dried in a vacuum oven at 40-45 °C to give compound 2 as a
white solid, mp 63-65 °C. IR (CHCl3) 2969, 1612, 1579, 1496,
1469, 1454, 1387, 1317, 1296, 1274, 12311, 1143, 1039, 839
3-(2-Cyanophenoxy)-2-propylphenol (3). To an appropriate
reactor was added DMSO (214.7 g, 195 mL, 4 vol), 2-propy-
lresorcinol (48.7 g), 2-fluorobenzonitrile (40.7 g, 35.7 mL, 1.05
equiv), and KOH (40.8 g, 2.0 equiv). The mixture was heated
to 40 °C for 6 h. After cooling to 20 °C, DI water (633 mL)
and Celite (6.3 g) were added. The mixture was filtered and
the wet cake washed with 1:1 DMSO/DI water (40.7 g, 37 mL).
To the filtrate was added 1.0 M HCl (319 mL, 1.0 equiv, 6.6
vol) over 3 h to pH 8.0-8.5, crystallizing the product. The
product was filtered, washed with 1:1 DMSO/DI water (80.4
g, 73 mL, 1.5 vol), followed by DI water (3 × 65 g, 4 vol).
The product was dried to a constant weight at 35-40 °C under
vacuum (10 mBar), to afford 3 (62.0 g, 76.5% yield), mp
116-118 °C. IR (CHCl3) 3601, 3008, 2965, 2934, 2233, 1600,
1577, 1495, 1449, 1280, 1248, 1161, 1108, 1097, 1037, 979
cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.65 (dd, J ) 7.5 Hz, J
) 1.43 Hz, 1 H), 7.44 (dt, J ) 7.11 Hz, J ) 1.48 Hz, 1 H),
7.15-7.0 (m, 2 H), 6.77 (d, J ) 8.51 Hz, 1 H), 6.70 (d, J )
8.0 Hz, 1 H), 6.54 (d, J ) 8.1 Hz, 1H), 5.25 (s, 1 H), 2.59 (t,
J ) 7.42 Hz, 2 H), 1.57 (qn, J ) 7.38 Hz, 2 H), 0.95 (t, 7.35
Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 160.2, 155.6, 153.7,
134.4, 133.8, 127.1, 122.3, 121.7, 116.10, 116, 112.6, 112.4,
102.7, 25.7, 22.5, 14.10; mass spectrum m/z (relative intensity)
253 (M+, 100). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.77;
N, 5.53. Found: C, 75.75; H, 5.79; N, 5.58.
2-[3-[3[[5-Ethyl-4′-fluoro-2-(phenylmethoxy)[1,1′-biphe-
nyl]-4-yl]oxy]-propoxy]2-propoxylphenoxy]benzonitrile (11).
A 25-mL three-necked round-bottomed flask was set up with
an overhead mechanical stirrer, water-cooled condenser, ther-
mocouple, heating mantle, and nitrogen inlet. To the flask was
charged 2 (2.08 g, 0.00495 mol, 1 equiv), 3 (1.27 g, 0.00501
mol, 1.01 equiv), followed by DMSO (12 mL, 6 vol), and 50%
NaOH (0.42 g, 0.00525 mol, 1.06 equiv). The mixture was
stirred under a nitrogen purge for 1 min. The reaction solution
was heated to 60 °C and stirred for 8 h. The reaction was then
allowed to cool to room temperature and filtered through a fine
scintered glass funnel to remove the precipitated salt. The
reaction flask and the filter cake/funnel were rinsed with hot
methanol (60 °C, 10 mL). The filtrate was transferred to a 50
mL three-necked round-bottomed flask equipped with an
overhead mechanical stirrer, water-cooled condenser, thermo-
couple, heating mantle, and nitrogen inlet. To the flask was
charged methanol (14 mL), and the solution was heated to 40
°C to ensure dissolution of any precipitated product. The
solution was allowed to cool, and the crystallized product was
isolated by suction-filtration and washed with cold methanol
(5 °C, 15 mL). The product (11) was dried in vacuo at 60 °C
overnight. Yield: 85%, mp 75-77 °C. IR (CHCl3) 2965, 2952,
2871, 2226, 1604, 1577, 1496, 1449, 1317, 1251, 1116, 1060,
839 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.63 (dd, J ) 7.75
Hz, J ) 1.47 Hz, 1 H), 7.60-6.90 (m, 13 H), 6.77 (d, J )
8.04 Hz, 1 H), 6.72 (d, J ) 8.65 Hz, 1 H), 6.58 (t, J ) 3.5 Hz,
2 H), 5.0 (s, 1 H), 4.24-4.16 (m, 4 H), 2.61 (q, J ) 7.70 Hz,
4 H), 2.35-2.28 (m, 2 H), 1.62-1.43 (m, 2 H), 1.20 (t, J )
7.43 Hz, 3 H), 0.89 (t, J ) 7.32 Hz, 3 H); 13C NMR (CDCl3,
75 MHz) δ 163.3, 160.2, 158.4, 156.6, 154.4, 153.4, 137.1,
134.5, 134.1, 133.8, 131.1, 130.9, 128.5, 127.7, 127.2, 126.9,
125.7, 123.8, 122.5, 122.2, 116.1, 115.9, 114.9, 114.6, 112.9,
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.6-7.46 (m, 2 H),
7.41-7.20 (m, 5 H), 7.15-7.05 (m, 3 H), 6.60 (s, 1 H), 5.04
(s, 2 H), 4.12 (t, J )5.74 Hz, 2 H), 3.78 (t, J ) 6.31 Hz, 2 H),
2.62 (q, J ) 7.47 Hz, 2 H), 2.28 (qn, J ) 6.0 Hz, 2 H), 1.22 (t,
J ) 7.53 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 163.4, 160.11,
156.4, 154.4, 137.2, 134.5, 131.1, 128.5, 127.8, 127.0, 125.7,
122.7, 114.9, 114.6, 99.1, 71.3, 64.5, 41.6, 32.3, 22.7, 14.5;
mass spectrum m/e (relative intensity) 398 (M+, 100). Anal.
Calcd for C24H24ClFO2: C, 72.26; H, 6.06; Cl, 8.89; F, 4.76.
Found: C, 72.27; H, 6.14; Cl, 9.45; F, 5.16.
274
•
Vol. 13, No. 2, 2009 / Organic Process Research & Development

108.2, 99.0, 71.2, 64.59, 64.8, 29.5, 25.7, 22.7, 22.6, 14.5, 14.3;
mass spectrum m/z (relative intensity) 615 (M+, 100). Anal.
Calcd for C40H38FNO4: C, 78.03; H, 6.22; F, 3.09; N, 2.27.
Found: C, 77.78; H, 6.22; F, 2.94; N, 2.36.
5.01 (br s, 1 H), 4.24 (t, J ) 6.27 Hz, 2 H), 4.20 (t, J ) 6.22
Hz, 2 H), 2.58 (m, 4 H), 2.4 (m, 2 H), 1.52 (m, 2 H), 1.17 (t,
J ) 7.56 Hz, 3 H), 0.90 (t, J ) 7.35 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 166.1, 163.8, 158.5, 157.7, 157.1, 152.5,
151.3, 134.9, 133.6, 133.3, 130.9, 130.8, 130.2, 127.5, 125.2,
124.2, 123.1, 118.9, 118.5, 116.3, 116.2, 113.2, 108.7, 99.7,
64.9, 64.3, 29.40, 25.8, 22.8, 22.7, 14.5, 14.2; mass spectrum
m/z (relative intensity) 544 (M+, 100). Anal. Calcd for
C33H33FO6: C, 72.78; H, 6.11; F, 3.49. Found: C, 72.76; H,
6.07; F, 3.22.
2-[3-[3[[5-Ethyl-4′-fluoro-2-hydroxyl[1,1′-biphenyl]-4-
yl]oxy]-propoxy]2-propoxylphenoxy]benzoic Acid (1). To a
methanolic (46 L) solution of compound 12 (2.3 kg, 4.39 mol)
was added sodium hydroxide (12.5 M, 24 L). This reaction
mixture was refluxed at 80 °C, for 12.5 h. After cooling to 5
°C, the reaction mixture was acidified to pH 0.44 with 12 N
hydrochloric acid (20 L). Methyl tert-butyl ether (3 × 30 L)
was used to extract the aqueous solution, and the combined
extracts were concentrated to a residue. The residue was
crystallized from acetonitrile (17.5 L) to provide 2.3 kg (99%)
of 1 as a white solid, mp 68-70 °C. IR (CHCl3) 3588, 3375,
2965, 2935, 2890, 1739, 1625, 1604, 1577, 1496, 1454, 1376,
Acknowledgment
We thank Kurt Lorenz and Marvin Hansen for helpful
discussions and the Physical Chemistry Department for provid-
ing analytical data.
1
1328, 1271, 1110, 1062, 843 cm-1; H NMR (CDCl3, 300
MHz) δ 8.23 (dd, J ) 7.86 Hz, J ) 1.73 Hz, 1 H), 7.55-7.05
(m, 7 H), 6.90 (s, 1 H), 6.81 (d, J ) 8.39 Hz, 1 H), 6.71 (d, J
) 8.45 Hz, 1 H), 6.62 (d, J ) 8.10 Hz, 1 H), 6.55 (s, 1 H),
Received for review October 8, 2008.
OP800257U
Vol. 13, No. 2, 2009 / Organic Process Research & Development
•
275