Synthesis of quinoline analogs: Search for antimalarial agents

Article abstract of DOI:10.1007/s00706-007-0772-5

Novel synthesis routes for the promising antimalarial agents 4(3-hydroxypyrrolidin-1-yl) and 4(3-hydroxypiperidine-1-yl)-2,8- bis(trifluoromethyl)quinoline have been developed.

Full text of DOI:10.1007/s00706-007-0772-5

Monatshefte fu¨r Chemie 139, 179–181 (2008)
DOI 10.1007/s00706-007-0772-5
Printed in The Netherlands
Synthesis of Quinoline Analogs: Search for Antimalarial Agents
Konda Ramesh Babu1, Begari Eeshwaraiah2, Dachepally Aravind2, Harshadas M. Meshram2,
Rallabaldi Madhusudan Raju3, Apurba Bhattacharya1, and Rakeshwar Bandichhor1;ꢀ
1
Center of Excellence, IPDO, Dr. Reddy’s Laboratories Ltd., Bollaram, India
2
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India
3
Department of Chemistry, Osmania University, Hyderabad, India
Received June 14, 2007; accepted July 23, 2007; published online December 24, 2007
# Springer-Verlag 2007
˚
It is known that the distance (approximately 3A)
Summary. Novel synthesis routes for the promising antimala-
rial agents 4(3-hydroxypyrrolidin-1-yl) and 4(3-hydroxy-
piperidine-1-yl)-2,8-bis(trifluoromethyl)quinoline have been
developed.
between the secondary alcohol and nonaromatic
secondary or tertiary amine functionalities in the
quinoline based antimalarial agents is crucial [3].
Based on this concept, we are actively involved
in the search of potential leads as antimalarial
agents. Our approach is to install all pharmacopho-
ric elements without changing significantly the qui-
noline framework. Here, we wish to report the
strategy involved in the racemic synthesis of struc-
tural type 1.
Keywords. Quinoline analogs; Antimalarial agents.
Background
Mefloquine, was an effective antimalarial agent first
introduced in 1971, that acts on the asexual intraery-
throcytic phase, one of the developmental stages of
malaria causing parasite [1]. More than a decade
before, a resistance of Plasmodium sp. emerged as
a potential threat to malaria therapy and this, togeth-
er with unavoidable side effects, e.g., CNS (central
nervous system) toxicity, have enforced physicians
not to prefer it for prescriptions that resulted in a
seldom use of this medicine [2]. Discovery of a cin-
chona alkaloid as an antimalarial agent played a piv-
otal role in the identification of lead structures that
incorporate a quinoline methanol unit. It is percepti-
ble that an emergence of mefloquine was a result of
SAR (structure activity relationship) studies based
on structural motif, as a pharmacophore, present in
the cinchona alkaloid.
Results and Discussion
The present work deals with the condensation of
substituted 4-haloquinolines 5 with cyclic amines that
led to a synthesis of novel quinoline derivatives 1.
The synthesis commences with the PPA mediated
condensation of substituted aniline with ethyl tri-
fluoroacetoacetate [4] that afforded corresponding 4-
hydroxyquinoline derivatives 3 [5]. Halogenation of
3 employing phosphorus oxyhalide or phosphorus
pentachloride yielded corresponding halo derivatives
5 [6]. Alternatively, haloquinones have been pre-
pared via tosyl derivatives [7].
Recently, it has been found that mefloquine enantio-
mers, (8R, 9S) and (8S, 9R), differ in their antimalarial
potentials. In vitro studies revealed that (þ)-(8S, 9R)-
has higher activity than (ꢁ)-(8R, 9S)-mefloquine [2].
To avoid the hazardous nature of transformation
of 3 to 5 employing phosphorus oxyhalide or phos-
phorus pentachloride, we opted to activate the phe-
nolic oxygen with a tosyl moiety to afford 4 and
substitute the ꢁOTs in it with an appropriate halide
nucleophile as presented in Scheme 1.
ꢀ
Corresponding author. E-mail: rakeshwarb@drreddys.com

180
K. Ramesh Babu et al.
Fig. 1. Similar pharmacophore structural motifs
Scheme 2
At first, the tosyl derivative 4 was prepared by
refluxing substituted 4-hydroxyquinoline and p-tolu-
enesulfonyl chloride (stoichiometric) in chloroform
in the presence of triethylamine for 20 h. Despite
of excellent yield (90%), the method itself was
not efficient because of prolonged refluxing and
tedious work-up. To improve the efficiency, acetone,
as a solvent, and NaOH, as a base, were used at 0ꢂC
to afford the tosylated product 4 in excellent yield
(91%).
The 4-bromoquinoline 5a was reacted separately
with hydroxypiperidine and hydroxypyrrolidine, as
shown in Scheme 2, to afford the corresponding ter-
tiary amine derivatives 1a and 1b in good yields.
Conclusion
In conclusion, we developed an efficient route for the
synthesis of quinoline analogs 1a and 1b. Syntheses of
chiral 4-aminoquinoline derivatives and biological acti-
vity testing of these compounds are under progress and
the extension of this work will be reported in future.
Experimental
Unless otherwise stated, all non-aqueous reactions and distil-
lations were carried out under an atmosphere of dry nitrogen
in dried glassware. When necessary, solvents and reagents
were dried prior to use. Analytical thin layer chromatography
(TLC) was performed on EM Reagents 0.25mm silica gel
aluminum support plates (Merck). Visualization was accom-
1
plished by irradiation under a 254 nm UV lamp. H NMR
spectra were recorded on a Varian 400MHz [1]. Chemical
shifts are reported in ppm from TMS (0ppm) or with the
solvent resonance as the internal standard (CDCl3 7.26ppm,
DMSO-d6 2.49 ppm, acetone-d6 2.04 ppm, benzene-d6
7.15 ppm). Data are reported as follows: chemical shift, mul-
tiplicity (s¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, app
qui ¼ apparent quintet, br ¼ broad, m ¼ multiplet), coupling
constants, and number of protons. IR spectra were taken on a
Perkin-Elmer equipment. Mass spectra were obtained on a low
resonance Q-trap machine in electron spray mode. Melting
points were obtained on a Polmon apparatus. Compounds
3–5 were prepared according to Refs. [4–7].
1-[2,8-Bis(trifluoromethyl)quinolin-4-yl]pyrrolidin-3-ol
(1a, C15H12F6N2O)
To a solution of 1.0 g (5a, 0.0031mol) in 5 cm3 DMF were
added 1.4 g 3-hydroxypyrrolidine (0.016 mol). The resulting
Scheme 1

Synthesis of Quinoline Analogs
181
solution was heated to 120ꢂC. After 2 h, the solvent was re-
moved under vacuum, the residue poured into water and ex-
tracted with ethyl acetate, washed with water, dried over
concentrated, Na2SO4 and chromatographed (SiO2; 30% ethyl
acetate=pet ether) to afford 0.89g 1a (75%). 1H NMR (CDCl3,
200 MHz): ꢀ ¼ 8.31 (d, 2H, J ¼ 8.7 Hz), 7.61 (m, 1H), 7.21 (s,
1H), 4.90 (s, 1H), 4.50 (s, 1H), 3.90–4.10 (m, 2H), 3.60–3.80
(m, 2H), 2.80–3.00 (m, 2H) ppm; IR (neat): ꢁꢀ¼ 3440, 1650,
1280 cmꢁ1; MS (FAB): C15H12F6N2O, m=z ¼ calcd 350.26,
found 349.00 (Mꢁ1)
ꢁꢀ¼ 3400, 1600, 1200 cmꢁ1; MS (FAB): C16H14F6N2O,
m=z ¼ calcd 364.29, found 365.00 (Mþ 1).
Acknowledgements
We thank IICT, Hyderabad for scientific and instrumental
support. B. Eeshwaraiah and D. Aravind thank CSIR, New
Delhi for the award of a Fellowship.
References
1-[2,8-Bis(trifluoromethyl)quinolin-4-yl]piperidin-3-ol
(1b, C16H14F6N2O)
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To a solution of 1.3 g (5a, 0.004 mol) in 8 cm3 DMF were
added 1.6 g 3-hydroxypiperidine (0.016mol). The resulting
solution was heated to 120ꢂC. After 2 h, the solvent was re-
moved under vacuum, the residue poured into water and
extracted with ethyl acetate, washed with water, dried over
sodium sulphate, concentrated, and chromatographed (SiO2;
30% ethyl acetate=pet ether) to afford 1b (1.15 g) in 78%
yield. 1H NMR (CDCl3, 200 MHz): ꢀ ¼ 8.31 (d, 2H, J ¼
8.7 Hz), 7.61 (m, 1H), 7.21 (s, 1H), 2.04–2.06 (m, 1H), 4.90
(s, 1H), 3.43–3.1 (m, 4H), 2.22–1.63 (m, 4H) ppm; IR:
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