Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid, a novel COX-2 inhibitor

Article abstract of DOI:10.1021/jo034274r

The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-2) inhibitor, is described. The synthesis relied on a novel indole formation that involved an alkylation/1,4-addition/elimination/isomerization cascade. It was demonstrated that the entire sequence from sulfonamide 13 and bromoketone 14 to the desired indole (1) could be executed in a single pot.

Full text of DOI:10.1021/jo034274r

Efficient Synthesis of
[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]-
acetic Acid, a Novel COX-2 Inhibitor
Ste´phane Caron* and Enrique Vazquez†
Chemical R&D, Pfizer Global Research & Development,
Groton, Connecticut 06340-8118
FIGURE 1. Synthetic target 1.
Rodney W. Stevens, Kazunari Nakao, Hiroki Koike, and
Yoshinori Murata
SCHEME 1
Medicinal Chemistry, Pfizer Global Research &
Development, 5-2 Taketoyo, Aichi 470-2393, Japan
stephane_caron@groton.pfizer.com
Received March 3, 2003
Abstract: The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-
indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-
2) inhibitor, is described. The synthesis relied on a novel
indole formation that involved an alkylation/1,4-addition/
elimination/isomerization cascade. It was demonstrated that
the entire sequence from sulfonamide 13 and bromoketone
14 to the desired indole (1) could be executed in a single
pot.
SCHEME 2
6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid
(1, Figure 1) was identified at Pfizer Global Research and
Development as a selective COX-2 inhibitor for the
potential treatment of pain and inflammatory-related
disorders.1,2 A synthesis amenable to multi-kilogram
scale was desired for this 6-chloroindole. Herein, we
present a practical and efficient synthesis of the desired
target, which includes a one-pot synthesis of the desired
indole nucleus.
The proposed retrosynthesis of 1 involved the elimina-
tion of a leaving group on nitrogen followed by isomer-
ization to generate the indole (Scheme 1). The desired
dihydroindole 2 could be obtained by a Michael addition
to an R,â-unsaturated ester 3 by a deprotonated keto-
aniline, which would result from the alkylation of a
protected aniline 4 with an R-haloketone 5.3 Ideally, the
protecting group used in the alkylation could be elimi-
nated in the last step. This strategy proved to be
successful for a variety of substrates.4
The first task was the identification of a suitable
synthesis of 4. The Discovery synthesis used a Wittig
olefination of nitroaldehyde 6 to obtain the desired alkene
according to the known procedure.5 Since we could not
identify a commercial source of the starting aldehyde for
large-scale synthesis, it was prepared from the corre-
sponding nitrotoluene derivative 7. Following Coe’s pro-
cedure,6 the methyl group was oxidized using DMF
dimethyl acetal to the dimethylenamine 8. While the
enamine could be isolated, it was more convenient to
oxidize it directly to the aldehyde 9 using aqueous NaIO4
in near-quantitative yield (Scheme 2).
A superior alternative that avoided the elevated tem-
perature reaction, high-energy intermediates, and the
Wittig reaction was also identified (Scheme 3). 2-Chloro-
5-bromonitrobenzene 10 was submitted to a Heck reac-
tion with ethyl acrylate leading to the desired cinnamate
11 in 95% yield. The nitro group could be chemoselec-
tively reduced with iron in the presence of ammonium
chloride affording the aniline 12 in 94% yield. Finally,
the sulfonamide 13 could be accessed under standard
methods in high yield. A sulfonamide was selected as a
protecting group because of some precedence for its use
as a leaving group in the formation of an indole.7
Interestingly, the Heck reaction did not proceed on the
† Current address: Merck & Co., Inc., RY-800-C367, P.O. Box 2000,
Rahway NJ 07065-0900.
(1) Reitz, D. B.; Seibert, K. Annu. Rep. Med. Chem. 1995, 30, 181-
188.
(2) Prasit, P.; Riendeau, D. Ann. Rep. Med. Chem. 1997, 32, 211-
220.
(3) Noe, C. R.; Knollmueller, M.; Schoedl, C.; Berger, M. L. Sci.
Pharm. 1996, 64, 577-590.
(4) Nakao, K.; Murata, Y.; Koike, H.; Uchida, C.; Kawamura, K.;
Mihara, S.; Hayashi, S.; Stevens, R. W. Submitted for publication.
(5) Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes,
C.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.;
Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Tricklebank, M. D.;
Saywell, K. L. J. Med. Chem. 1993, 36, 3397-3408.
(6) Vetelino, M. G.; Coe, J. W. Tetrahedron Lett. 1994, 35, 219-
222.
(7) Wojciechowski, K.; Mieczyslaw, M. Synthesis 1992, 571-576.
10.1021/jo034274r CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003
4104
J. Org. Chem. 2003, 68, 4104-4107

SCHEME 3
SCHEME 4
SCHEME 5
sulfonamide analogous to 10 (obtained from a reduction
with Raney-nickel and hydrazine8 and treatment with
TsCl).
The next challenge was the formation of the indole.
The classical procedure for the preparation of this
heterocycle is the Fisher indole synthesis.9 Recently, a
number of new synthetic methods have been published
on the topic.10-14 Our approach begins with the alkylation
of sulfonamide 13. Several solvents and bases were
evaluated, and K2CO3 in dimethyl acetamide (DMAC)
proved to be the optimal combination. Both the R-bromo
and R-chloro ketones were investigated, and it was found
that while the reaction took only a few minutes with the
bromide, it necessitated over a day with the chloride.
When sulfonamide 13 was treated with 1.1 equiv of
bromo ketone 14 and 2.0 equiv of K2CO3 in DMAC, the
sulfonamide was rapidly alkylated and the Michael
reaction proceeded to provide the dihydroindole 15 in less
than 30 min. However, elimination of the toluenesulfinic
acid was slow under these conditions. This was circum-
vented by addition of a stronger base, such as 1 N NaOH,
to the reaction mixture, which allowed for the elimination
and isomerization to the indole to proceed as well as for
the hydrolysis of the ethyl ester to the desired target.
The isolation of the product in pure form proved to be
straightforward. The sodium salt of 1 is very water
soluble such that once the hydrolysis of the ester was
completed, the reaction mixture was extracted with
methyl tert-butyl ether (MTBE), which allowed for re-
moval of the DMAC and other organic materials. The
aqueous layer was acidified to pH 1 with HCl, and
carboxylic acid 1 was extracted with EtOAc. After
concentration of the extracts, the product was crystallized
isolated as a 9:1 mixture of trans and cis isomers. Finally,
if the entire reaction was performed in K2CO3 in DMAC
and DBU was added in place of NaOH, indole 17 was
isolated in 81% yield. The ethyl ester could then easily
be cleaved to the carboxylic acid 1 using NaOH in MeOH
and water. The only intermediate that was never ob-
served is imine 18, which must rapidly isomerize to the
indole (Scheme 5).
An efficient preparation of 6-chloro-2-(4-chlorobenzoyl)-
1H-indol-3-ylacetic acid (1) has been demonstrated. The
route implemented relied on a novel indole formation,
which involves four tandem reactions. The precursor to
this sequence, acrylate 13, can be prepared efficiently
through a Heck reaction. This synthesis is amenable to
the preparation of a variety of indoles since the three
components (an aniline, a Michael acceptor, and an
R-haloketone) are all easily accessible.4
Experimental Section
General Methods. Unless otherwise noted, starting materi-
als were obtained from commercial suppliers and used without
further purification. Silica gel chromatography was carried out
with J. T. Baker 40 mm silica gel according to Still’s procedure.15
Thin-layer chromatography was performed with EM Separations
Technology silica gel F254, and HPLC was performed with a
Hewlett-Packard Series 1100 using a Puresil C18 column (4.6 ×
150 mm) and 50/50 or 80/20 CH3CN/H2O mobile phase. Melting
points were measured in open capillary tubes and are uncor-
i
in PrOH/H2O to afford 1 in 82% yield (Scheme 4).
The indole formation proceeds through several inter-
mediates, most of which could be observed and even
isolated by modifying the reaction conditions. For in-
stance, if the potassium salt of sulfonamide 13 was first
prepared, the alkylated product 16 could be isolated in
76% yield. Furthermore, if this product was resubmitted
to K2CO3 in DMAC, the dihydroindole 15 could be
1
rected. H NMR and 13C NMR were measured in CDCl3 unless
otherwise indicated. Coupling constants (J) are reported in hertz.
IR spectra were recorded as thin films on NaCl plates unless
otherwise indicated.
2-Nitro-4-chlorobenzaldehyde (6). A solution of 2-nitro-4-
chlorotoluene (7) (25.0 g, 122 mmol) and DMF‚DMA (48.6 mL,
366 mmol) was heated at 135 °C (external oil bath temperature)
for 11 h. The reaction mixture was cooled to room temperature
and added dropwise to a 20 °C solution of NaIO4 (78.0 g, 365
(8) Wiese, D.; Tacke, R.; Wannagat, U. Liebigs Ann. Chem. 1981,
1285-1293.
(9) Robinson, B. The Fisher Indole Synthesis; John Wiley & Sons:
New York, 1982.
(10) Tokunaga, M.; Ota, M.; Haga, M.-a.; Wakatsuki, Y. Tetrahedron
Lett. 2001, 42, 3865-3868.
(11) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 10251-10263.
(12) Cho, S. C. Tetrahedron 2001, 57, 3321-3329.
(13) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org.
Chem. 2001, 66, 1403-1412.
(15) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
(14) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
J. Org. Chem, Vol. 68, No. 10, 2003 4105

mmol) in water (250 mL) and DMF (125 mL).16 After 3 h, the
crude reaction mixture was filtered, and the solids were washed
with toluene (250 mL). The filtrate was transferred to a
separatory funnel, and the layers were separated. The organic
layer was washed with water (3 × 250 mL) and concentrated to
an oil. Hexanes (30 mL) were added, and the desired product
was crystallized. The solid was filtered to afford 2-nitro-4-
chlorobenzaldehyde (6) (22.4 g, 99% yield), which was identical
(120 mL) were added K2CO3 (9.45 g, 68.4 mmol) and 2′-bromo-
4-chloroacetophenone (14) (8.78 g, 37.6 mmol). The reaction was
stirred at room temperature for 15 min. NaOH (1 N, 130 mL)
was added, and the reaction mixture was heated to 100 °C for 8
h. The reaction mixture was cooled to room temperature, poured
into a separatory funnel, and washed with MTBE (2 × 200 mL).
The aqueous layer was acidified to pH 1 with 6 N HCl and was
extracted with EtOAc (150 mL). The solvent was removed under
reduced pressure, and to the resulting oil were added iPrOH (24
mL) and water (48 mL). A solid precipitated, and the slurry was
stirred 12 h. The solid was filtered, washed with water, and dried
to provide [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid
(1) (9.73 g, 82%): mp 181-183 °C; 1H NMR (400 MHz, DMSO-
d6) δ 3.79 (s, 2H), 7.08 (dd, 1H, J ) 8.5, 1.9), 7.42 (d, 1H, J )
1.9), 7.60 (d, 2H, J ) 8.5), 7.62-7.73 (m, 3H), 11.74 (bs, 1H),
12.22 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ 31.74, 113.25,
118.00, 121.93, 123.96, 127.69, 130.10, 131.30, 132.02, 133.59,
138.02, 138.37, 138.58, 173.20, 188.29; IR 3314, 1710, 1700,
1
to the reported H NMR spectrum.17
3-(4-Chloro-2-nitrophenyl)acrylic Acid Ethyl Ester (11).
To 2-chloro-5-bromonitrobenzene (10) (30.0 g, 127 mmol), Pd-
(OAc)2 (285 mg, 1.27 mmol), and PPh3 (666 mg, 2.54 mmol) in
DMF (360 mL) were added Et3N (24.7 mL, 178 mmol) and ethyl
acrylate (138 mL, 1.27 mol). The reaction was stirred at 87 °C
for 10 h, cooled to room temperature, and poured into a
separatory funnel containing toluene (300 mL). The mixture was
washed with 1 N HCl (300 mL) and water (2 × 200 mL). The
organic extracts were concentrated to an oil that was crystallized
in hexanes (60 mL). The solid was filtered to afford 3-(4-chloro-
2-nitrophenyl)acrylic acid ethyl ester (11) (30.8 g, 95%): mp )
1618, 1522, 1323, 1227, 1093, 941 cm-1. Anal. Calcd for C17H11
-
Cl2NO3: C, 58.64; H, 3.18; N, 4.02. Found: C,58.58; H, 3.22; N,
3.93.
1
64-65 °C; H NMR (300 MHz) δ 1.38 (t, 3H, J ) 7.2), 4.32 (q,
2H, J ) 7.2), 6.39 (d, 1H, J ) 15.9), 7.60-7.67 (m, 2H), 8.04-
8.09 (m, 2H); 13C NMR (100 MHz) δ 14.14, 60.96, 123.86, 125.01,
128.94, 130.06, 133.51, 136.08, 138.43, 165.41; IR 1715, 1523,
1291, 1046 cm-1. Anal. Calcd for C11H10ClNO4: C, 51.68; H, 3.94;
N, 5.48. Found: C, 51.68; H, 4.17; N, 5.25.
3-[4-Chloro-2-(N-chlorophenyl)-2-oxoethyl]-N-(4-tolu-
enesulfonylamino)]acrylic Acid Ethyl Ester (16). To a
solution of 3-[4-chloro-2-(4-toluenesulfonylamino)phenyl]acrylic
acid ethyl ester (13) (3.00 g, 7.90 mmol) in DMAC (15.0 mL)
were added K2CO3 (2.18 g, 15.8 mmol) and 2′-bromo-4-chloro-
acetophenone (14) (2.03 g, 8.69 mmol). The reaction was stirred
for 30 min, poured into 1 N HCl (30 mL), and extracted with
MTBE (2 × 30 mL). The organic extracts were dried over MgSO4,
filtered, concentrated to a low volume. Hexanes was added and
a solid precipitated. The precipitate was filtered to provide 3-[4-
chloro-2-N-(4-chlorophenyl)-2-oxoethyl]-N-(4-toluenesulfonylami-
no)]acrylic acid ethyl ester (16) (3.19 g, 76%): mp ) 162-165
°C; 1H NMR (300 MHz) δ 1.38 (t, 3H, J ) 7.2), 2.47 (s, 3H), 4.28
(q, 2H, J ) 7.2), 5.00 (bs, 2H), 6.23 (d, 1H, J ) 16.0), 7.29-7.36
(m, 4H), 7.47 (d, 2H, J ) 8.7), 7.54 (d, 1H, J ) 8.4), 7.59 (d, 2H,
J ) 8.3), 7.74 (d, 1H, J ) 16.0), 7.88 (d, 2H, J ) 8.7); 13C NMR
(75 MHz) δ 14.33, 21.62, 57.72, 60.66, 112.49, 120.69, 128.07,
129.21, 129.58, 129.70, 131.22, 132.80, 133.83, 134.80, 135.84,
138.55, 139.28, 140.38, 144.46, 166.02, 191.70; IR 1720, 1698,
3-(4-Chloro-2-aminophenyl)acrylic Acid Ethyl Ester (12).
To 3-(4-chloro-2-nitrophenyl)acrylic acid ethyl ester (11) (10.8
g, 42.2 mmol) in EtOH (151 mL) and H2O (43 mL) were added
iron powder (325 mesh) (7.10 g, 127 mmol) and NH4Cl (1.35 g,
25.2 mmol). The reaction was stirred at 85 °C for 1 h, cooled to
room temperature, and filtered through Celite. The filter cake
was washed with toluene (200 mL), and the filtrate was
concentrated to a low volume (∼50 mL), diluted with toluene
(150 mL), and washed with H2O (2 × 100 mL). The organic
extracts were dried over MgSO4, filtered, and concentrated to a
solid that was triturated with hexanes (25 mL). The solid was
filtered to afford 3-(4-chloro-2-aminophenyl)acrylic acid ethyl
ester (12) (8.71 g, 91%): mp ) 69-71 °C; 1H NMR (300 MHz) δ
1.36 (t, 3H, J ) 7.2), 4.08 (bs, 2H), 4.29 (q, 2H, J ) 7.2), 6.35 (d,
1H, J ) 15.7), 6.72-6.77 (m, 2H), 7.29-7.36 (m, 1H), 7.75 (d,
1H, J ) 15.7); 13C NMR (75 MHz) δ 14.33, 60.59, 116.18, 118.30,
118.53, 119.09, 129.21, 136.77, 138.85, 146.37, 167.08. IR 3389,
3347, 3240, 2987, 1698, 1627, 1319, 1185, 796 cm-1. Anal. Calcd
for C11H12ClNO2: C, 58.54; H, 5.36; N, 6.21. Found: C, 58.63;
H, 5.41; N, 6.21.
3-[4-Chloro-2-(4-toluenesulfonylamino)phenyl]acrylic
Acid Ethyl Ester (13). To 3-(2-amino-4-chlorophenyl)acrylic
acid ethyl ester (12) (18.0 g, 79.8 mmol) in CH2Cl2 (144 mL) were
added pyridine (9.04 mL, 112 mmol) and p-TsCl (16.0 g, 83.9
mmol). The reaction was stirred at room temperature for 18 h
and poured into 1 N HCl (150 mL). The layers were separated,
and the organic layer was dried over MgSO4, filtered, and
concentrated. Hexanes was added to the resulting solid and
filtered to afford 3-[4-chloro-2-(4-toluenesulfonylamino)phenyl]-
acrylic acid ethyl ester (13) (28.3 g, 93%): mp ) 124-127 °C;
1H NMR (300 MHz) δ 1.35 (t, 3H, J ) 7.2), 2.40 (s, 3H), 4.27 (q,
2H, J ) 7.2), 6.12 (dd, 1H, J ) 15.9, 0.9), 7.20-7.39 (m, 4H),
7.39 (d, 1H, J ) 8.6), 7.48-7.53 (m, 2H), 7.62 (d, 2H, J ) 8.3);
13C NMR (75 MHz) δ 15.50, 22.79, 62.24, 122.48, 127.98, 128.49,
129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55,
167.59; IR 3214, 1694, 1631, 1318, 1167 cm-1. Anal. Calcd for
1590, 1338, 1313, 1179, 1161, 1089 cm-1. Anal. Calcd for C26H23
-
Cl2NO5S: C, 58.65; H, 4.35; N, 2.63. Found: C, 58.74; H, 4.56;
N, 2.72.
cis- and trans-[6-Chloro-2-(4-chlorobenzoyl)-1-(4-tolu-
enesulfonyl)-2,3-dihydro-1H-indol-3-yl]acetic Acid Ethyl
Ester (15). To 3-[4-chloro-2-(N-chlorophenyl)-2-oxoethyl]-N-(4-
toluenesulfonylamino)]acrylic acid ethyl ester (16) (1.00 g, 1.88
mmol) in DMAC (5.0 mL) was added K2CO3 (0.520 g, 3.76 mmol).
The reaction mixture was stirred for 4 h, poured in 1 N HCl (30
mL) and extracted with MTBE (2 × 30 mL). The organic extracts
were dried with MgSO4, filtered, and concentrated. The resulting
solid was purified by chromatography on silica gel (EtOAc/
hexanes 20/80) to provide [6-chloro-2-(4-chlorobenzoyl)-1-(4-
toluenesulfonyl)-2,3-dihydro-1H-indol-3-yl]acetic acid ethyl ester
(15) as a 1:9 mixture of cis and trans isomers (0.488 g, 49%).
Some of the 1H NMR (300 MHz) significant signals are: δ 1.09
(t, J ) 7.2), 1.19 (t, J ) 7.2), 2.44 (s), 5.40 (d, J ) 4.0), 5.99 (d,
J ) 9.7), 6.92 (dd, J ) 8.1, 1.1), 7.04 (dd, J ) 8.1, 1.9), 7.52 (d,
J ) 8.4), 7.57 (d, J ) 1.9), 7.73 (d, J ) 8.3), 7.99 (d, J ) 8.6).
LC-MS analysis was performed on the mixture of diastereoi-
somers and indicated to products with identical mass of 531 (M
+ H+).
[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid
Ethyl Ester (17). To a solution of 3-[4-chloro-2-(4-toluenesulfo-
nylamino)phenyl]acrylic acid ethyl ester (13) (3.00 g, 7.90 mmol)
in DMAC (15.0 mL) were added K2CO3 (2.18 g, 15.8 mmol) and
2′-bromo-4-chloroacetophenone (14) (2.03 g, 8.69 mmol). The
reaction was stirred for 30 min, and DBU (3.54 mL, 23.7 mmol)
was added. The reaction mixture was stirred 1 h, poured into 1
N HCl (30 mL), and extracted with MTBE (2 × 30 mL). The
organic extracts were dried with MgSO4, filtered, and concen-
trated to provide a solid that was stirred in a mixture of MTBE
and hexanes to afford [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-
yl]acetic acid ethyl ester (17) (2.42 g, 81%): mp ) 186-188 °C;
C
18H18ClNO4S: C, 56.91; H, 4.78; N, 3.69. Found: C, 57.10; H,
5.08; N, 3.70.
[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid
(1). To a solution of 3-[4-chloro-2-(4-toluenesulfonylamino)-
phenyl]acrylic acid ethyl ester (13) (13.0 g, 34.2 mmol) in DMAC
(16) The quench of this reaction is exothermic but can be controlled.
The internal temperature did not rise above 26 °C when it was
performed in a flask placed in a 20 °C bath.
(17) Ahmad, A.; Dundar, L. J.; Green, I. G.; Harvey, I. W.; Shepherd,
T.; Smith, D. M.; Wong, R. K. C. J. Chem. Soc., Perkin Trans. 1 1994,
19, 2751-2758.
4106 J. Org. Chem., Vol. 68, No. 10, 2003

1H NMR (300 MHz) δ 1.27 (t, 3H, J ) 7.1), 3.80 (s, 2H), 4.11 (q,
2H, J ) 7.1), 7.15 (ddd, 1H, J ) 8.5, 1.7, 0.5), 7.28-7.30 (m,
1H), 7.48 (d, 2H, J ) 8.3), 7.54-7.57 (m, 1H), 7.77 (d, 2H, J )
8.3), 9.16 (bs, 1H); 13C NMR (75 MHz) δ 15.42, 32.29, 62.45,
113.27, 117.60, 122.99, 123.23, 127.85, 130.12, 131.77, 133.61,
137.86, 138.13, 140.10, 172.45, 188.25; IR 3305, 1732, 1618, 1323
cm-1. Anal. Calcd for C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72.
Found: C, 60.70; H, 3.97; N, 3.71.
[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid
(1) from 17. To a solution of [6-chloro-2-(4-chlorobenzoyl)-1H-
indol-3-yl]acetic acid ethyl ester (17) (200 mg, 0.532 mmol) in
MeOH (2 mL) and water (0.8 mL) was added NaOH (137 mg,
3.43 mmol). The reaction mixture was stirred for 24 h and was
concentrated to a low volume. Water (4 mL) was added, and the
material was transferred to a separatory funnel and was washed
with CH2Cl2 (5 mL). The aqueous layer was acidified to pH 1
with 1 N HCl and was extracted with EtOAc (15 mL). The
organic layer was dried over MgSO4, filtered, and concentrated
to afford [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid
(1) (150 mg, 81%). The 1H NMR spectrum was identical with
the one obtained for the compound prepared by the method
described earlier.
JO034274R
J. Org. Chem, Vol. 68, No. 10, 2003 4107