Development of an efficient process for 4,5,7-trichloroquinoline, a key intermediate for agrochemical synthesis

Article abstract of DOI:10.1021/op010111y

A short, simple, and industrially feasible process for the preparation of 4,5,7-trichloroquinoline, starting from 3,5-dichloroaniline and acrylonitrile, in essentially three steps, is discussed. This article presents the preparative process, including the

Full text of DOI:10.1021/op010111y

Organic Process Research & Development 2002, 6, 242−245
Development of an Efficient Process for 4,5,7-Trichloroquinoline, A Key
Intermediate for Agrochemical Synthesis
B. Chandrasekhar,* A. S. R. Prasad, S. Eswaraiah,† and A. Venkateswaralu
Process Research and Technology DeVelopment, Dr. Reddy’s Research Foundation, Bollaram Road,
Miyapur, Hyderabad-500 050, India
Scheme 1
Scheme 2
Abstract:
A short, simple, and industrially feasible process for the
preparation of 4,5,7-trichloroquinoline, starting from 3,5-
dichloroaniline and acrylonitrile, in essentially three steps, is
discussed. This article presents the preparative process, includ-
ing the impurity profile, of each intermediate.
Introduction
The marked antimalarial activity of a number of quinoline
derivatives1 having an aminoalkyl side chain attached in the
fourth position (2) led to an investigation of new procedures
for the preparation of 4-chloroquinolines, which in turn may
be readily converted to the desired drug.2 One such inter-
mediate, 4,5,7-trichloroquinoline (1) (Scheme 1) was de-
scribed as a useful intermediate for the preparation of
pyrimidinylthiopyrimidinyloxy quinoline derivatives (3) and
phenoxyalkane carboxylates (4), which are reported as potent
herbicides,3a microbicides,3b,c and fungicides.3d-h
In view of these properties, it has created some interest
among synthetic organic chemists, culminating in the de-
velopment of several synthetic routes.4a-i
Results and Discussion
Of all the schemes reported in the literature, we selected
three routes for study on the basis of their seemingly simple
* Author for correspondence. Telephone: 91-40-3045439. Fax: 91-40-
3045438. E-mail: chandrasekharb@drreddys.com.
chemistry. The first route1b (Scheme 2) consists of five steps.
The first step is based on Conrad-Limpach methodology5
of the reaction of 3,5-dichloroaniline (5) and ethyl oxalo-
acetate (6) (â-ketoester) to afford the corresponding Schiff
base ethyl â-arylaminomaleate (7). The Schiff base on
thermal cyclisation in medicinal mineral oil at 250 °C yields
5,7-dichloro-4-hydroxyquinoline-2-carboxylic ethyl ester (8),
which on hydrolysis yields the corresponding hydroxy acid
† Present address: Dr. Reddy’s Laboratories, 7-1-27 Ameerpet, Hyderabad-
500 016, India.
(1) (a) Andersag, H.; Brietner, S.; Jung, H. Ger Patent 683,792, 1939; Chem.
Abstr. 1942, 36, 4973. (b) Surray A.; Hammer H. F. J. Am. Chem. Soc.
1946, 68, 1244. (c) Price, C. C.; Roberts, R. M. J. Am. Chem. Soc. 1946,
68, 1204.
(2) (a) Singh, T.; Stein, G. R.; Biel, H. J.; J. Med. Chem. 1969, 12 (5), 801. (b)
Heindel, N. D.; Bechara, I.; Ohnmacht, J. C.; J. Med. Chem. 1969, 12 (5),
797. (c) Sen, A. K.; J. Indian Chem. Soc. 1967, 44 (7), 597. (d) Duphar
International Research B. V. Neth. Appl. 7,904,723 (cl.c07D401/04), 1980;
Chem. Abstr. 1981, 95, 251324.
(3) (a) Serban, A.; Watson, G. K. Eur. Pat. Appl. (cl.c07D215/22) 1981, EP
29,319; Chem. Abstr. 1981, 95, 115319q. (b) Shimotori, H.; Yanase, J.;
Tomura, N.; Sekina, T.; Kuno Y.; Yoshikawa, Y. Jpn. Kokai Tokkyo Koho
JP 05,301,806, 1993; Chem. Abstr. 1994, 120, 156701a. (c) Yoshikaw, Y.;
Ishii, T.; Tanigawa, H.; Maeda, S.; Kawashima, H.; Ishikawa, K. Jpn. Kokai
Tokkyo Koho, JP 06,49,061, 1994; Chem. Abstr. 1994, 121, 134148c. (d)
Arnold, R. W.; Coghlan, J. M.; Krumklans, V. E.; Jourdan, P. G.;. Suhr, G.
R. Eur. Pat. Appl. 1989, EP 326,330; Chem. Abstr. 1990, 112, 35883y. (e)
Ishikawa, K.; Yoshikawa, Y.; Ishii, T.; Tanikawa, H.; Maeda, S.; Ka-
washima, H.; Yanase, Y.; Shinitori, H.; Mita, R.; Eur. Pat. Appl. (clc07D401/
12), 1992, EP 497,371; Chem. Abstr. 1992, 117, 191862z. (f) Yoshikawa,
Y.; Ishii, T.; Tanigawa, H.; Maeda, S.; Kawashima, H.; Ishikawa, K.;
Yanase, J. Jpn. Kokai Tokkyo Koho JP 06,49,064, 1994; Chem. Abstr. 1994,
121, 134142y. (g) Yoshikawa, Y.; Ishii, T.; Tanigawa, H.; Maeda, S.;
Kawashima, H.; Ishikawa, K.; Yanase, J.; Shimotori, H.; Tomura, N. Jpn.
Kokai Tokkyo Koho JP 06,56,824, 1994; Chem. Abstr. 1994, 121, 35623z.
(h) Roberg, L. R.; Alt, A. C.; DeAminis, V. C. U.S. Patent 5,245,036, 1993;
Chem. Abstr. 1994, 120, 30682n.
(4) (a) Surrey, A. R.; U.S. Patent 2,555,943, 1951; Chem. Abstr. 1951, 45, 9568.
(b) Geo, L. F.; Gardner, S. W. U.S. Patent 2,520,041, 1950; Chem. Abstr.
1951, 45, 672. (c) Martin, H. E.; Theodora, S. F. U.S. Patent 2,579,320,
1951; Chem. Abstr. 1952, 46, 7126. (d) Tong, C. Y. J. Heterocycl. Chem.
1970, 7 (1), 171. (e) Degener, E.; Holtschmidt, H. Ger. Patent. 2,213,238,
1973; Chem. Abstr. 1973, 79, 146422s. (f) Takuma, J.; Tanaka, T. Jpn.
Kokai Tokkyo Koho, JP 07,258,216, 1995; Chem. Abstr. 1994, 124,
145929y. (g) Adaway, J. T.; Budd, T. J.; King, R. I.; Krumell, L. K.;
Kershner, D. L.; Maurer, L. J.; Olmstead, A. T.; Rotu, A. G.; Tai, J. J.;
Hadd, A. M. WO 98/33774, 1998; Chem. Abstr. 1998, 129, P148917g. (h)
Wendell, A. G.; Michael, J. C.; Glen, J. P.; Eriks, K. V.;. Robert, S. G.
U.S. Patent 5,145,843, 1992; Chem. Abstr. 1990, 112, 35883y. (i) Rosskelly,
T.; Maguike, M. P. Tetrahedron, 1985, 41 (15), 3033.
(5) (a) Conrad, M.; Limpach, L. Ber. 1887, 20, 944. (b) Limpach, L. Ber. 1931,
64, 969. (c) Rubstov; Lisgunova, J. Gen. Chem., USSR 1943, 13, 697. (d)
Elderfield, R. C. Heterocyclic Compounds; John Wiley & Sons Inc.: New
York, 1952; Vol. IV, pp 1-343. (e) Reitsema, R. H. Chem. ReV. 1948, 43,
43.
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10.1021/op010111y CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/06/2002

Scheme 3
Scheme 4
Scheme 5
(9), followed by decarboxylation in mineral oil at 270 °C
which gives the 5,7-dichloro-4-hydroxyquinoline. Chlorina-
tion of 10 with POCl3 results in 4,5,7-trichloroquinoline (1).
This route worked very well in terms of chemistry, but
we encountered problems in scaling up the process. In
addition, we observed the following drawbacks which
rendered this route less attractive.
1. Compound 7 (â-anilinoacrylate) is a liquid, the
purification of which needs high-vacuum distillation at high
temperature, resulting in the partial charring and loss in the
yields.
2. In the synthesis, the ring-closure reaction is a high-
temperature process, not preferred for scale-up.
3. The use of mineral oil in this high-temperature process
also leads to a messy process in work up.
The second route1c (Scheme 3) involves the reaction of
3,5-dichloroaniline (5) with ethoxymethylene malonic ester
(11) in the first step.6,7,4g The resulting anilinomethylene
malonate of the formula (12) upon thermal cyclization in
Dowtherm or diphenyl ether gives 4-hydroxy-3-carboxy-
quinoline derivative (13). The ester on hydrolysis gives the
4-hydroxyquinoline-3-carboxylic acid (14). The thermal
decarboxylation of hydroxy acid (14) resulted in the forma-
tion of 4-hydroxy-5,7-dichloroquinoline (10), which on
chlorination with phosphorus oxychloride produces 4,5,7-
trichloroquinoline (1).
Although Scheme 3 appeared to be straightforward with
a better overall yield of 15% compared to that of the first
route of overall yield 12% (Scheme 2), but the following
shortcomings are noted:
(1) Ethoxymethylene malonic ester (EMME) is relatively
expensive.
(2) In this case also the thermal cyclization is not an
efficient process due to the product decomposition and
reaction work up.
(3) Isolation of (13) from Dowtherm A or diphenyl ether
appeared to be tedious on large scale.
The third route4h (Scheme 4) starts with reaction of 3,5-
dichloroaniline (5) with Meldrum’s acid derivative (15),
which upon thermolysis undergoes ring opening, elimination
of acetone, and subsequent cyclization to give 5,7-dichloro-
4-hydroxyquinoline (10). Chlorination with phosphorus oxy-
chloride produces 4,5,7-trichloquinoline (1).
Even this route is not free from problems. The main
drawbacks are the following:
(1) Preparation of Meldrum’s acid derivative adds one
extra step to the process, and this is also a relatively
expensive raw material.
(2) Thermolysis in plant-scale operations leads to product
decomposition.
An Alternative Route. A new route has been developed
to simplify the process and to make it cost effective and
feasible for scale-up operation. This involves five steps and
utilizes acrylonitrile in the first step as shown in Scheme 5.
Stage I. Cyanoethylation8,9 of various alkyl and alkoxy
anilines using acrylonitrile in acetic acid medium has been
reported in the literature. We observed that â-anilinopro-
pionitriles have been employed as starting materials for the
synthesis of various alkyl, alkoxychloro quinolines. Hence,
it was decided to employ the â-anilinopropionitrile for the
synthesis, which must eliminate decarboxylation step, as the
required three-carbon chain comes from acrylonitrile. We
(6) Price, C.; Royston, R. M. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. I, p 272.
(7) Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890.
(8) Merchant, J. R.; Chottnia, D. S. J. Chem. Soc., Perkin Trans. 1 1972, 932.
(9) Heininger, S. A. Organic Syntheses; Wiley: New York, 1963; Collect. Vol.
4, p 146.
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attempted the reaction of 3,5-dichloroaniline (5) with acry-
lonitrile (17) at 90-100 °C, and the Michael addition
proceeded to near completion affording â-anilinopropionitrile
(18) in 82% yield and 97% purity (HPLC). The use of
acrylonitrile and copper acetate not only simplified the
process but also proved to be less expensive. LC-MS
analysis of the residue after distillation indicated the presence
of the following bis-cyanoethylated aniline (21) in traces.
Stage V. The conversion of 5,7-dichloro-4-hydroxyquino-
line (10) to 4,5,7-trichloroquinoline (1) was readily achieved
using phosphorus oxychloride. 4,5,7-Trichloroquinoline (1)
so obtained in 90% yield was of high quality (99% purity
by HPLC).
Scale-Up Trials. With the procedure fully optimized, for
stage I to stage V of Scheme 5, the scale-up trials were
performed at 5-10 kg scale. This route was operated
routinely without problems. The expected yields and purities
obtained in all stages of the synthesis demonstrate the
robustness and viability of the process.
Conclusions
A short, simple, and inexpensive industrially feasible
process for the preparation of the 4,5,7-trichloroquinoline
has been developed. Preparation of 5,7-dichloro-4-hydroxy-
quinoline (10) and 4,5,7-trichloroquinoline (1) have been
simplified without compromising on their yield and purity.
Stage II. â-Anilinopropionitrile (18) was hydrolysed in
10% aqueous sodium hydroxide solution and without isolat-
ing the sodium salt, the reaction mass was neutralized by
treatment with concentrated hydrochloric acid to give
â-anilinopropionic acid (19) in about 90% yield, with a
HPLC purity of ∼99%. The aqueous phase was freeze-dried
for LC-MS analysis which revealed the formation of (22)
as an impurity.
Experimental Section
Solvents and reagents were obtained from commercial
sources and were used as such without any further purifica-
tion unless specified. The melting points are recorded on
Buchi-535 apparatus and are uncorrected. The 1HNMR
spectra were obtained using a 200 MHz Varian Gemini
spectrometer using tetramethylsilane as internal standard.
Infrared spectra were recorded using a Perkin-Elmer model
1640 instrument. Mass spectra were recorded on an MS
Engine-Hewlett-Packard model 5989 at DIP 20 eV. HPLC
equipment consisted of a Waters 510 pump, a Waters 486
UV-vis detector, a Waters 746 data module, and a Bond-
clone C-18 column.
Stage III. The cyclization of â-anilinopropionic acid (19)
was accomplished in polyphosphoric acid. The reaction was
facile, and product 20 was obtained in 80% yield. The purity
of the compound 20 is 99%. The LC-MS analysis of the
mother liquors indicated the presence of the following
impurity (23).
Preparation of 3,5-Dichloroanilino-â-propionitrile (18).
Thirty-two and four tenths kilograms of 3,5-dichloroaniline,
10.6 kg of acrylonitrile, and 2.04 kg of cupric acetate
monohydrate were suspended in a 100-L reactor. The
reaction mass was stirred and heated to 80-90 °C for a
period of 6-8 h. Progress of the reaction was monitored by
TLC. The reaction mixture was cooled to room temperature,
and the resulting dark mixture was quenched with 40 L of
NH4OH solution until the pH reached 8-8.5. The reaction
mixture was extracted with toluene (3 × 200 L), washed
with water (3 × 40 L), and distilled. The crude 3,5-
dichloroanilino-â-propionitrile was distilled to give 35.1 kg
of the pure compound: bp 180-200 °C/3-5 mm, yield 82%,
mp 76-78 °C, purity 99% by HPLC [HPLC system:
BondcloneC18 column; mobile phase: 0.01 M KH2PO4/
MeOH in 45:55 ratio; flow rate 0.8 mL/min; λ 254 nm,
Stage IV. 5,7-Dichloro-2,3-dihydroquinolin-4-(1H)-one
(20) on dehydrogenation10a-e with 5% Pd/C in refluxing 1,2-
dichlorobenzene gave (10) in about 78% yield with 99%
HPLC purity. The Pd/C was separated from the precipitated
product by extraction with 10% methanolic sodium hydrox-
ide and the insoluble 5% Pd/C was filtered, dried, and
recycled three times. The methanolic sodium hydroxide was
neutralized with concentrated HCl to obtain pure 5,7-
dichloro-4-hydroxyquinoline (10). In this way the purification
of the compound 10 and separation of Pd/C for recycling
was achieved.
1
retention time 7.68 min]. IR cm-1 3470, 2250. H NMR
(CDCl3) δ 2.5 (t, 3H), 3.4 (t, 3H), 4.3 (broad singlet, 1H),
6.7-7.2 (m, 3H). Mass spectrum m/z 214 corresponding to
C9H8Cl2N2.
Preparation of 3,5-Dichloroanilino-â-propionic Acid
(19). 3,5-Dichloroanilino-â-propionitrile (18) (10.7 kg) and
40 L of 10% sodium hydroxide solution were suspended in
a 100-L reactor. The reaction mixture was heated to 90-95
°C for a period of 8-10 h until there was no further evolution
of ammonia in the reaction. The reaction mixture was cooled
(10) (a) Backwall, J. E.; Ploback, N. A. J. Org. Chem. 1990, 55, 4528. (b) Polema,
B.; Gribble, G. W. Tetrahedron Lett. 1990, 31, 2381. (c) Horrey, R. G.;
Pataki, J.; Corteg, C.; Diruddo, P.; X. C. Yang, J. Org. Chem. 1991, 56,
1210. (d) Peet, N. P.; LeTournean; M. E. H. 1991, 32, 41. (e) Somon S. S.;
Trivedi K. N. J. Indian Chem. Soc. 1990, 67, 997.
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and then acidified with concentrated hydrochloric acid
(10 L) for pH of 5.8-6.0 and extracted with toluene
(25 L × 3). The toluene extracts were again washed with
water (25 L × 2). The organic layer was concentrated to a
volume of 15-20 L, and the precipitated 3,5-dichloroanilino-
â-propionic acid (19) was filtered, dried to give 10.4 kg of
19: yield 90%, purity 97% [HPLC system: BondcloneC18
150 mm column; mobile phase: 0.01 M KH2PO4/MeOH in
45:55 ratio; flow rate 0.8 mL/min; λ 254 nm, retention time
5.37 min], mp 102-104 °C. IR cm-1 3470, 1720. 1H NMR
(CDCl3) δ 2.5-3.6 (t, 2H), 3.2-3.4 (t, 2H), 5.0 (broad
singlet, 1H), 6.5-7.4 (m, 3H). Mass spectrum m/z 233
corresponding to C9H9Cl2NO2.
To separate the Pd/C from the product, the product was
extracted with 10% methanolic sodium hydroxide (∼10 L),
and the insoluble 5% Pd/C was filtered and dried. The
methanolic sodium hydroxide was neutralized with concen-
trated HCl (∼2.5 L) until the pH reached 5.8-6.0. The
precipitated product was filtered and dried to afford 4.13 kg
of 10: yield 78%, purity 97-98% by HPLC [HPLC
system: Bondclone C18 150 mm column; mobile phase: 0.01
M KH2PO4/MeOH in 45:55 ratio; flow rate 0.8 mL/min; λ
254 nm, retention time 6.85 min], mp 345-48 °C. IR (cm-1)
3450, 1620; 1H NMR (CDCl3 + TFA) δ 7.51 (d, 1H), 7.63
(d, 1H), 8.03 (d, 1H), 8.67 (d, 1H); MS m/z 213 corresponds
to C9H5Cl2NO.
Preparation of 5,7-dichloro-2,3-dihydroquinolin-4-
(1H)-one (20). Phosphorus pentoxide (8 kg) and 6.7 L of
orthophosphoric acid were placed into 50-L reactor. The
mixture was heated to 100 °C for 2 h, and 4.66 kg of 3,5-
dichloroanilino-â-propionic acid (18) was added slowly in
about 30 min. The reaction mixture was maintained at 90-
100 °C for 2 h. Progress of the reaction was monitored by
TLC. The reaction mixture was brought to room temperature,
chilled water (20 L) was added, and the mixture was
extracted with toluene (10 L × 3). The organic layer was
washed with water and concentrated to a volume of 4-6 L.
The precipitated product was filtered and dried to give 3.4
kg of 20: yield 80%, purity 98% [HPLC system: Bond-
cloneC18 150 mm column; mobile phase: 0.01 M KH2PO4/
MeOH in 45:55 ratio; flow rate 0.8 mL/min; λ 254 nm,
retention time 5.85 min], mp 184-186 °C. IR (cm-1) 3470,
Preparation of 4,5,7-Trichloroquinoline (1). 5,7-Dichloro-
4-hydroxyquinoline (10) (6.39 kg), 30 L of toluene, and 3.1
L of phosphorus oxychloride were placed into a 50-L reactor.
The reaction mixture was heated to 120-130 °C under
stirring and maintained for 1 h. The progress of the reaction
was monitored by TLC. The reaction mixture was cooled to
room temperature. The toluene layer was washed with water
(9 L × 3) until the pH reached 6-7. The toluene layer was
concentrated to a minimum volume of 3-6 L and cooled to
5-10 °C. The precipitated product was filtered and dried to
give 6.24 kg of 1: yield 90%, purity 99% by HPLC [HPLC
system: SGE column; mobile phase: hexane/dioxane in 9:1
ratio; flow rate 2 mL/min; λ 254 nm, retention time 3.39
min], mp 104 °C. 1H NMR (CDCl3) δ 7.51 (d, 1H), 7.63 (d,
1H), 8.03 (d, 1H), 8.67 (d, 1H). Mass spectrum m/z 231
corresponds to C9H4Cl3N.
1
1720. H NMR (CDCl3) δ 2.8 (m, 2H), 3.63 (m, 2H), 6.3
(s, 1H), 7.1 (s, 1H). Mass spectrum m/z 215 corresponding
Acknowledgment
to C9H7Cl2NO.
We acknowledge the support of Dr. Reddy’s Group of
Companies for their many practical contributions, both in
the laboratory and in the pilot plant. We thank Mr. G. V.
Prasad for his constant help and encouragement. We also
thank Dr. G. Om Reddy for his valuable scientific inputs.
Preparation of 5,7-Dichloro-4-hydroxyquinoline (10).
5,7-Dichloro-2,3-dihydroquinolin-4-(1H)-one (20) (5.37 kg),
0.8 kg of 5% Pd/C, and 12.5 L of 1,2-dichlorobenzene were
placed into 50-L reactor. The reaction mixture was stirred
and heated to 180-200 °C for 12-14 h, monitoring the
progress of the reaction by TLC. The reaction mixture was
cooled to room temperature, and the precipitated solid
5,7-dichloro-4-hydroxyquinoline (10), was filtered and dried.
Received for review December 11, 2001.
OP010111Y
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