A new route to prepare 6-chloro-5-(2-chloroethyl)oxindole

Article abstract of DOI:10.1021/op020095k

6-Chloro-5-(2-chloroethyl)oxindole, a key intermediate in the manufacturing of the antipsychotic drug, ziprasidone, has been synthesized by a new route. The salient features of the synthesis are (1) bis-dialkylation of 2,4-difluoro-5-chloronitrobenzene with sodium diethyl malonate, (2) decarboxylative hydrolysis to obtain the oxindole derivative, and (3) reduction and chlorination of acetic ester side chain.

Full text of DOI:10.1021/op020095k

Organic Process Research & Development 2003, 7, 309−312
A New Route to Prepare 6-Chloro-5-(2-chloroethyl)oxindole
Mukund K. Gurjar,* A. M. S. Murugaiah, and Dandepally Srinivasa Reddy
National Chemical Laboratory, Pune 411 008, India
Mukund S. Chorghade
Chorghade Enterprises, 14, Carlson Circle, Natick, Massachusetts 01760, U.S.A.
Abstract:
This synthesis suffers from two limitations:
6-Chloro-5-(2-chloroethyl)oxindole, a key intermediate in the
manufacturing of the antipsychotic drug, ziprasidone, has been
synthesized by a new route. The salient features of the synthesis
are (1) bis-dialkylation of 2,4-difluoro-5-chloronitrobenzene with
sodium diethyl malonate, (2) decarboxylative hydrolysis to
obtain the oxindole derivative, and (3) reduction and chlorina-
tion of acetic ester side chain.
(a) The intermediate ω-chloroacetophenone derivative 4
is an irritant, and on large-scale manufacturing process it
may pose handling difficulties.
(b) The use of triethylsilane reagent for reduction of the
benzylic ketone is expensive.
New Route. On the basis of these limitations, we devised
a new synthetic route for the key intermediate 5, in which
the ω-chloroacetophenone derivative 4 and the use of
triethylsilane were circumvented.
Introduction
The basic premise of our synthetic approach is based on
SNAr reaction of aromatic halides with a carbon nucleophile.
For example, we had recently reported6 that halogen atoms
present at the ortho and para positions of nitrohalobenzenes
can be conveniently displaced with the sodium salt of diethyl
malonate to give aryl-substituted malonate esters in good
yield. The meta-substituted nitrohalobenzene does not un-
dergo such a substitution reaction. Therefore, our first choice
was to conduct the substitution reaction of 2,4,5-trichloro-
nitrobenzene (7) with an excess of the sodium salt of diethyl
malonate in DMF. This reaction gave a 2:1 mixture of
monoalkylated products (8a and 8b), with a trace of
dialkylated product (10).
Ziprasidone hydrochloride1 is a serotonin and dopamine
antagonist, and effective as an antipsychotic drug. Ziprasi-
done does not increase the weight of the patient and therefore
has a distinctive advantage. Many currently available anti-
psychotic drugs have the side effect of inducing significant
weight gain, which is distressing and stigmatizing to patients
and increases the risk of cardiovascular complications.2
Ziprasidone is indeed a superior drug that was recently
approved by the Food and Drug Administration of the United
States.3
Since fluorine is a better leaving group, particularly when
activated by a nitro group,7 we envisaged that 5-chloro-2,4-
difluoronitrobenzene (9), easily obtainable from 2,4,5-tri-
chloronitrobenzene (7) and activated KF in DMF,8 would
be an ideal precursor for dialkylation reactions. Indeed, the
reaction of 9 with the sodium salt of diethyl malonate gave
the dialkylated product 10, as sole product. However,
subsequent decarboxylative elimination of 10 turned out to
be a difficult proposition. For instance, the decarboxylation
of 10 under Krapcho’s conditions (NaCl, H2O, DMSO, 160
°C)9 or with its modified conditions (MgCl2‚6H2O, DMA,
140 °C)10 resulted in the formation of m-xylene (11) and
toluene derivatives (12). Formation of these compounds was
due to the bis(dealkoxycarbonylation) of diethyl malonate
group under the influence of the electron-withdrawing nitro
substituent. (Scheme 2).6
Previous Work. Ziprasidone was earlier prepared4 by a
route described in Scheme 1. The synthesis involves Wolf-
Kishner reduction of 6-chloroisatin (2) to give 6-chloroox-
indole (3). Subsequent treatment with chloroacetyl chloride
and AlCl3 under Freidel-Crafts conditions provided 5-chlo-
roacetyl-6-chlorooxindole (4). The ketone functionality of
4 was reduced using triethylsilane in trifluoroacetic acid to
produce 6-chloro-5-(2-chloroethyl)oxindole (5). The alky-
lation reaction between 5 and 65 in the presence of Na2CO3
in water followed by salt preparation with aqueous hydro-
chloric acid gave ziprasidone hydrochloride.
(1) Drugs Future 1994, 19, 560.
(2) Howard, H. R.; Seeger, T. F. Novel Antipsychotics. Annu. Rep. Med. Chem.
1993, 28, 39.
(6) Gurjar, M. K.; Reddy, D. S.; Murugaiah, A. M. S. Synthesis 2000, 1659.
(7) Zhu, J. Synlett 1997, 133.
(3) Press release from Food and Drug Administration: Washington, DC, 2000.
(4) Lowe, J. A., III; Nagel, A. A. U.S. Patent 4,831,031; Bowles, P. U.S. Patent
5,206,366.
(8) (a) King, F. E.; Clark-Lewis, J. W. J. Chem. Soc. 1953, 172. (b) Mason,
J.; Milner, D. J. Synth. Commun. 1994, 24, 529. (c) Smyth, T. P.; Carey,
A.; Hodnett, B. K. Tetrahedron 1995, 51, 6363.
(5) Walinsky, S. W.; Fox, D. E.; Lambert, J. F.; Sinay, T. G. Org. Process
Res. DeV. 1999, 3, 126.
(9) Krapcho, A. P. Synthesis 1982, 805.
(10) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
10.1021/op020095k CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/20/2003
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Scheme 1a
a Reagents and Conditions: a) NH2NH2, EtOH. b) ClCH2COCl, AlCl3, CH2Cl2. c) Et3SiH, CF3CO2H. d) (i) Na2CO3, H2O. (ii) HCl, H2O
Scheme 2a
a Reagents and Conditions: a) Na+CH-(CO2Et)2, DMF, 100 °C, 12 h. b) KF, cetrimide, DMF, 125 °C, 12 h. c) NaCl, H2O, DMSO, 160 °C, 12 h or MgCl2‚6H2O,
DMA, 140 °C, 7 h.
The formation of these byproducts, 11 and 12, prompted
us to modify the reaction conditions. The hydrolysis of aryl
malonate derivative (10) was carried out by refluxing with
6 N HCl and glacial acetic acid which provided the requisite
derivative 13. It was converted into the dimethyl ester 14
using thionyl chloride in methanol and fully characterized
by analytical and spectroscopic methods.
Subsequent hydrogenation of the nitro group in 14 was
carried out with Raney nickel in acetic acid to provide the
oxindole derivative 15 in excellent yield. Reduction of 15
with LiBH4 prepared in situ and catalytic B(OMe)3 in
refluxing THF provided11 the alcohol 16 which was con-
verted into 6-chloro-5-(2-chloroethyl)oxindole 5 by two
methods. 16 was first converted into the tosylate derivative
17, which on exposure to LiCl in DMF provided the target
molecule 5: mp 222 °C, lit.4 mp 210-211 °C. Alternatively,
conversion of alcohol 16 into the chloro derivative 5 was
effected in one step with triphenylphosphine in refluxing
CCl4 (Scheme 3).
avoids both the irritant intermediate (4) and the use of
triethylsilane.
Experimental Section
General Methods. Starting materials and reagents were
purchased from Aldrich, Fluka, or Lancaster and used as
received. TLC was performed on precoated silica gel plates
(E-Merk, 60 F254) and visualized by UV irradiation or
spraying with anisaldehyde or phosphomolybdic acid stains
followed by charring on a hot plate. NMR spectra were
recorded on Bruker spectrometers (AC 200, MSL 300) with
TMS as an internal standard. IR spectra were obtained from
Perkin-Elmer 16 PC-FTIR spectrophotometer. EI mass
spectra were recorded on Finngan MAT-1020. Combustion
data were recorded on Elmentar-Vario-EL (Heraeus Com-
pany Ltd., Germany). Melting points were measured on
Buchi 535 melting point apparatus.
5-Chloro-2,4-difluoronitrobenzene (9). Toluene was
distilled from the mixture of potassium fluoride (38.2 g, 657
mmol), cetrimide (5.94 g, 17.6 mmol), DMF (250 mL), and
dry toluene (100 mL) to remove traces of moisture. 2,4,5-
Trichloronitrobenzene (7) (50.0 g, 220 mmol) was added and
heated at 125 °C for 12 h under N2. The reaction mixture
was cooled, diluted with water, and extracted with ethyl
acetate. The organic layer was washed with brine, dried (Na2-
Conclusions
We have developed a new route to an advanced inter-
mediate (5) for the antipsychotic drug, ziprasidone, which
(11) Brown, H. C.; Choi, Y. M.; Narasimhan, S. Inorg. Chem. 1981, 20, 4454.
310
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Scheme 3a
a Reagents and Conditions: a) 6 N HCl, AcOH, reflux, 18 h. b) SOCl2, MeOH, rt, 4 h. c) Raney Ni, H2 (45 psi), AcOH, rt, 3 h. d) LiBH4, B(OMe)3, THF, reflux,
18 h. e) TsCl, Et3N, DMAP, CH2Cl2, reflux, 5 h. f) LiCl, DMF, 50 °C. g) TPP, CCl4, THF, reflux, 3 h.
SO4), and evaporated to give a residue, which was distilled
Methyl 6-Chloro-(2-oxindol-5-yl)acetate (15). A solu-
tion of 14 (16 g, 53 mmol) in acetic acid (80 mL) containing
1.6 g of Raney nickel was hydrogenated at 45 psi for 3 h.
After the catalyst was filtered, acetic acid was distilled to
afford solid which was recrystallized from 2-propanol to
under vacuo to provide 9 (23.5 g, 55%), bp ) 83 °C at 0.5
1
Torr, lit. bp ) 85 °C at 0.5 Torr; H NMR (CDCl3, 200
MHz) δ 7.18 (t, 1 H, J ) 9.2 Hz), 8.24 (t, 1 H, J ) 7.4 Hz).
Tetraethyl 4-Chloro-6-nitro-1,3-benzenedimalonate (10).
Sodium diethyl malonate (52.0 g, 285 mmol) and 9 (20.0 g,
103 mmol) in DMF (125 mL) were heated at 100 °C for 12
h. The reaction mixture was cooled and acidified with 10%
dilute HCl. Water was added to the reaction, extracted with
ethyl acetate, washed with brine, dried (Na2SO4), and
concentrated. The crude product 10 (46.0 g, 94%) was used
directly in the next reaction. A small portion of the crude
product was chromatographed on silica gel with ethyl
1
afford pure 15 (12 g, 94%): mp ) 191-192 °C; H NMR
(acetone-d6, 200 MHz) δ 3.48 (s, 2 H), 3.67 (s, 3 H), 3.77
(s, 2 H), 6.96 (s, 1 H), 7.27 (s, 1 H), 10.72 (s, 1 H); IR
(Nujol) 1722, 1676 cm-1. Anal. Calcd for C11H10ClNO3: C,
55.13; H, 4.21; N, 5.85. Found: C, 55.08; H, 4.17; N, 5.84.
6-Chloro-5-(2-hydroxyethyl)-2-oxindole (16). A mixture
of sodium borohydride (4.74 g, 125 mmol) and lithium
bromide (10.87 g, 125 mmol) in THF (150 mL) was refluxed
for 16 h with vigorous stirring. Oxindole ester 15 (15.0 g,
62.6 mmol) and B(OMe)3 (0.7 mL, 6.2 mmol) were added,
and refluxing continued for 18 h. The reaction mixture was
concentrated and acidified with 3 N sulphuric acid and solid
filtered to afford 16 (10 g, 75%): mp ) 178-179 °C; IR
(Nujol) 1716 cm-1; 1H NMR (acetone-d6, 200 MHz) δ 2.70-
2.90 (m, 2 H), 3.40 (s, 2 H), 3.60-3.77 (m, 2 H), 6.85 (s, 1
H), 7.17 (s, 1 H), 9.3 (br s, 1 H); EI MS (m/z) 211 [M+].
Anal. Calcd for C10H10ClNO2: C, 56.75; H, 4.76; N, 6.62.
Found: C, 56.63; H, 4.97; N, 6.39.
1
acetate-petroleum ether (1:5) as eluent to give pure 10: H
NMR (CDCl3, 200 MHz) δ 1.31 (t, 12 H, J ) 7.27 Hz),
4.28 (m, 8 H), 5.21 (s, 1 H), 5.27 (s, 1 H), 7.70 (s, 1 H),
8.15 (s, 1 H); IR (Nujol) 1715 cm-1; MS (m/z) 473 [M+].
4-Chloro-6-nitro-1,3-benzenediacetic Acid (13). A mix-
ture of 10 (46.0 g, 97 mmol), 6 N HCl (125 mL) and glacial
acetic acid (125 mL) was heated under reflux for 18 h, cooled
and concentrated in vacuo to provide a solid which was
recrystallised from ethyl acetate-light petroleum to give 13
1
(24.0 g, 90%): mp ) 193-194 °C; H NMR (acetone-d6,
200 MHz) δ 3.9 (s, 2 H), 4.10 (s, 2 H), 7.60 (s, 1 H), 8.15
(s, 1 H); IR (Nujol) 1685 cm-1. Anal. Calcd for C10H8-
ClNO6: C, 43.90; H, 2.95; N, 5.12. Found: C, 44.14; H,
2.92; N, 4.94.
6-Chloro-5-(2-chloroethyl)-2-oxindole (5). Method A.
A mixture of 16 (10.8 g, 51 mmol), TsCl (11.7 g, 61.4
mmol), triethylamine (11 mL), and DMAP (0.2 g) in CH2-
Cl2 (200 mL) was refluxed for 5 h and concentrated, and
the residue was passed through a silica gel pad (30% ethyl
Dimethyl 4-Chloro-6-nitro-1,3-benzenediacetate (14).
Thionyl chloride (3 mL, 5.5 mmol) was added dropwise to
a solution of 13 (15.0 g, 55 mmol) in methanol (150 mL).
The reaction mixture was stirred at room temperature for 4
h, rendered neutral with sodium bicarbonate solution, and
then concentrated to remove excess of methanol. The residue
was extracted with ethyl acetate, washed with brine, dried
(anhydrous Na2SO4), and evaporated. The solid residue was
recrystallized from methanol to give 14 (15.7 g, 95%): mp
1
acetate in hexane) to obtain 17 (16.0 g, 85%); H NMR
(CDCl3, 200 MHz) δ 2.43 (s, 3 H), 3.02 (t, 2 H, J ) 4.3
Hz), 3.43 (s, 2 H), 4.21 (t, 2 H, J ) 4.3 Hz), 6.83 (s, 1 H),
7.01 (s, 1 H), 7.27 (d, 2 H, J ) 6.5 Hz), 7.67 (d, 2 H, J )
6.5 Hz), 9.10 (s, 1 H).
17 (16 g, 43.7 mmol) and LiCl (18.54 g, 437 mmol) in
DMF (80 mL) were heated at 50 °C for 8 h, diluted with
water, and extracted with diethyl ether. The ether layer was
washed with brine, dried (Na2SO4), and concentrated. The
residue was filtered through silica gel column with EtOAc-
light petroleum (1:1) as eluent to give 5 (9.55 g, 95%): mp
1
) 107-108 °C; H NMR (CDCl3, 200 MHz) δ 3.70 (s, 3
H), 3.75 (s, 3 H), 3.85 (s, 2 H), 3.95 (s, 2 H), 7.30 (s, 1 H),
8.20 (s, 1 H); IR (Nujol) 1724 cm-1. Anal. Calcd for C12H12-
ClNO6: C, 47.78; H, 4.01; N, 4.64. Found: C, 47.64; H,
3.95; N, 4.68.
1
) 222 °C, lit.4 mp ) 210-211 °C; H NMR (acetone-d6,
200 MHz) δ 3.15 (t, 2 H, J ) 7.1 Hz), 3.45 (s, 2 H), 3.77
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(t, 2 H, J ) 7.1 Hz) 6.93 (s, 1 H), 7.28 (s, 1 H), 9.95 (br s,
1 H); EI MS (m/z) 231 [M + 1]
purified on silica gel as described above to give 5 (1.48 g,
97%).
Method B. A mixture of 16 (1.4 g, 6.6 mmol), triphenyl-
phosphine (2.6 g, 9.9 mmol) in THF (17 mL) and CCl4 (3
mL) was refluxed for 3 h and concentrated. The residue was
Received for review November 18, 2002.
OP020095K
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