Simple and effective route for synthesis of parvaquone, an antiprotozoal drug

Article abstract of DOI:10.1039/c4ra09934f

Parvaquone, an antiprotozoal agent against Theileria parva, was synthesized in 33.8% overall yield by using cheap, commercially available raw materials. A key intermediate, 2-cyclohexyl-1-naphthol, was synthesized in 86% yield by cyclohexylation of 1-naphthol and further converted into parvaquone in good yield through reaction sequences such as oxidation and epoxidation followed by isomerization.

Full text of DOI:10.1039/c4ra09934f

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Simple and Effective Route for Synthesis of Parvaquone, an Antiprotozoal Drug
Pravin C. Patil and Krishnacharya G. Akamanchi*
Parvaquone, an antiprotozoal agent against Theileria parva, was synthesized in 33.8% overall yield by using cheap
and commercial raw materials. Key intermediate, 2-cyclohexyl-1-naphthol was synthesized in 86% yield by
cyclohexylation of 1-naphthol and further converted into parvaquone in good yield through reaction sequences such
as oxidation, epoxidation followed by isomerization.
OH
O
•
•
•
•
Overall yield 33.8%
OH
OH
Safe & environmentally benign
Cheap & easily accessible reagents
Avoids transition metals & hazardous peroxides
p-TSA
OH
Parvaquone, 1
O
2-cyclohexyl-1-naphthol
1-naphthol

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Simple and Effective Route for Synthesis of Parvaquone, an
Antiprotozoal Drug
Pravin C. Patila and Krishnacharya G. Akamanchi*
Cite this: DOI: 10.1039/x0xx00000x
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DOI: 10.1039/x0xx00000x
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Parvaquone, an antiprotozoal agent against Theileria parva, was First method for free radical mediated alkylation of naphthoquinone
synthesized in 33.8% overall yield by using cheap and
commercial raw materials. Key intermediate, 2-cyclohexyl-1-
naphthol was synthesized in 86% yield by cyclohexylation of 1-
naphthol and further converted into parvaquone in good yield
through reaction sequences such as oxidation, epoxidation
was developed by Fieser et al in 1946 by generation of free radical
from corresponding diacyl peroxide in the presence of 2-hydroxy-1,
4-naphthoquinone (Lawson) to give corresponding alkylated
naphthoquinones.7 Developed method provided inferior yield (5 to
6%) of alkylated naphthoquinones and generate numerous side
products during the course of reaction. However these protocols
were not applied toward synthesis of parvaquone 1.
In 1951, Fieser et al further developed a method for synthesis of 1
by generating cyclohexyl radical from cyclohexanecarboperoxoic
acid A in the presence of lawson provide 1 in 45% yield2 (Scheme 1,
Method a). In 1968, Amini et al modified Fieser’s general method
for alkylation of naphthoquinone by replacing corresponding diacyl
peroxide with tert-butyl peroxide in respective hydrocarbons and the
developed protocol was extended toward synthesis of 1 by using
cyclohexane B in combination with tert-butyl peroxide in presence
of lawson8 (Scheme 1, Method b). In continuation toward further
development, Khambay et al demonstrated new method for synthesis
of 1 through generating cyclohexyl radical from cyclohexane
carboxylic acid C using silver nitrate/ammonium persulfate in the
presences of lawson and afforded 1 in 25 % yield9 (Scheme 1,
Method c).
followed by isomerization
.
Naphthoquinones and substituted naphthoquinones articulate
spectrum of wide-ranging biological activities such as antibacterial,
antifungal, anti-inflammatory, antithrombotic, antiplatelet, antibiotic,
antiallergic, and apoptosis.1 Naphthoquinones substituted with
alicyclic ring at 2 or 3 positions are deliberated as highly effective
agents for the suppression of trophozoites in ducks, chickens,
canaries and monkeys infected with mosquito or blood-induced
malaria. These compounds are capable of destroying fully developed
exoerythrocytic forms of malaria parasites.2
Theileriosis (East Coast Fever), a disease in cattles caused by
microscopic parasite Theileria parva and majorly found in central
and eastern Africa. Theileriosis is among the most concerned
livestock diseases in Africa causing an annual loss of 1.1 million
cattles and more than 250 million to be at risk.3 The disease resulted
in high mortality rate up to the 1970s due to the lack of effective
treatment and mortality can be up to 100%, with death occurring
within a month after the initial attachment of infected ticks.4 2-
cyclohexyl-1,4-naphthoquinone (Parvaquone, 1) and 2-((4-tert-
butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone
O
Method a. A, CH3COOH, 100 0C, 45%
Method b. B, (CH3)3COOC(CH3)3, 53%
Method c. C, AgNO3, (NH4)S2O8, 25%
O
OH
OH
(Buparvaquone) have been effectively used since their discovery in
the treatment of Theileriosis.3,4 Parvaquone, marketed as Clexon, is
an analogue for menoctone which had been identified as having anti-
theilerial activity against Theileria parva.5 Unfortunately, due to
complexity of structure and high cost of manufacturing prohibited
further development of menoctone. Recently, resistance of Theileria
parva to buparvaquone has been reported.6 By considering these
limitations related with menoctone and buparvaquone, importance of
parvaquone is significantly evolving.
O
O
Parvaquone, 1
Lawson
O
O
Where
OH
OH
O
C =
B =
A =
Scheme 1 Different routes for cyclohexyl radical mediated synthesis of
parvaquone starting from Lawson.
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA09934F
Besides cyclohexyl radical mediated transformations, new
During literature survey related to synthesis of parvaquone, we
approach for the synthesis of 1 has been disclosed by Leach and identified that the most significant challenge was introduction of
Urquhart et al by condensing 1,4-isochromandione with cyclohexyl moiety and therefore an alternative key intermediate, 4
7
cyclohexanecarbaldehyde 8 followed by rearrangement of resulting was selected toward simplification of cyclohexylation process.
aldol product using sodium methoxide in methanol to afford overall Cyclohexylation of naphthol has been reported by catalytic methods
77.3% yield of 110 (Scheme 2).
using catalysts such as zinc chloride,12a (Scheme 4, path a), Retrol
(an acid activated bleaching earth)12b (Scheme 4, path b), cation
exchange resin (Scheme 4, path c),12c and montmorillonite12d
(Scheme 4, path d) in the presence of various cyclohexylating
counterparts such as cyclohexanol, cyclohexene and cyclohexanone.
Most of these reported methods possesses disadvantages of affording
O
H
O
O
NH4OAc, AcOH
NaOMe, MeOH
O
+
23 h, rt, 77.3%
OH
O
O
7
8
1
very low yield and necessity of high temperature.
"Prior art"
Scheme
2
Synthesis of parvaquone through condensation of 1,4-
isochromandione with cyclohexanecarbaldehyde.
a. Cyclohexanol, Zinc chloride
b. Cyclohexanol, Retrol
or
or
Most of these single step transformations for synthesis of 1 retains
shortcomings such as necessity of specialized starting materials, use
of hazardous peroxides in presence of oxidants, harsh reaction
conditions, costly raw materials and afford low yields due to
byproduct formations, especially in free radical mediated routes.2, 8-9
To overcome on aforementioned meagernesses, multistep synthesis
through ring construction approach have been recently established
by Pena-Carrera et al for synthesis of 111a and its derivatives11b
starting from diisopropyl squarate. Use of Grignard reagents,
cryogenic reaction conditions, use of trifluoroacetic anhydride,
boron tribromide under inert atmosphere restricted this process from
being industrially fisible. Considering these inadequacies, the
development of adaptable method for synthesis of 1 using cheap raw
materials and mild reaction conditions at open atmosphere still
remains a significant challenge.
We herein report a simple and effective synthesis of parvaquone
developed from cheap and commercially available raw materials. A
new reaction system has been established for the synthesis of
key intermediate, 2-cyclohexyl-1-naphthol 4, by cyclohexylation of
1-naphthol 2 using cyclohexanol 3 in presence of p-toluenesulfonic
acid. Obtained 4 was oxidized by using mild oxidant such as 30%
hydrogen peroxide in presence of hydrochloric acid to afford 2-
cyclohexyl-1, 4-naphthoquinone 5. Resulted compound 5 was
further converted into parvaquone, 1 by epoxidation followed by
isomerization. The general synthetic route is depicted in Scheme 3.
OH
OH
c. Cyclohexene, Cation exchange resin or
d. Cyclohexanone, Montmorillonite
e. Cyclohexanol, p-TSA, Solvent
2
4
"This method"
Scheme 4 Different approaches for synthesis of 2-cyclohexyl-1-naphthol.
With this background, we attempted an alternative approach for
synthesis of 4. Based on the preliminary observations from trial
experiments, cyclohexanol was chosen as cyclohexylating agent over
cyclohexene and cyclohexyl halides. The reactions of 2 with 3 were
carried out in solvents such as toluene, xylene and chlorobenzene at
their boiling point temperature in the presence of p-toluenesulfonic
acid (Scheme 4, path e). Among these solvents, chlorobenzene was
selected as the best solvent since cyclohexylated product 4 was
obtained in highest yield of 86% while toluene and xylene were
provided 53% and 42% yields of 4 respectively under the same set of
reaction conditions. To our notification, reaction in chlorobenzene
below 80 °C did not initiate conversion. When reaction of 2 with 3
was
carried
out
under
neat
conditions
by
using
p-toluenesulfonic acid at 95 °C, desired compound 4 was isolated in
38% yield.
By keeping chlorobenzene constant in the role of reaction solvent,
further optimization was carried out to select appropriate acid
catalyst for this transformation. The reactions of 2 with 3 were
carried out by using various acid catalysts such as p-toluenesulfonic
acid (p-TSA), methanesulfonic acid (MSA), sulfuric acid, tungstate
sulfuric acid (TSA) and phosphomolybdic acid and the results are
summarized in Table 1. Among the listed acids used, p-
toluenesulfonic acid mediated cyclohexylation reaction afforded the
highest yield of 4 in 86% (Table 1, entry 1) while the lowest yield
was obtained from tungstate sulfuric acid mediated cyclohexylation
reaction (Table 1, entry 4). Methanesulphonic acid mediated
cyclohexylation provided average yield of 4 in 56% (Table 1, entry
2), while inferior yields were isolated from sulfuric acid and
phosphomolybdic acid mediated cyclohexylation reactions (Table 1,
entry 3 and 5, respectively).
OH
OH
O
O
OH
3
30% H2O2
Conc. HCl
p-TSA
5
2
4
30% H2O2 /
Na2CO3
O
O
Conc. H2SO4
O
OH
O
1
O
6
Scheme
3 Synthetic strategy for parvaquone synthesis starting from
1-naphthol.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA09934F
Table
1
Optimization of acid catalyst towards synthesis of
2-cyclohexyl-1-naphthol
Notes and references
Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Matunga, Mumbai-400 019, India.
Tel.: +91-22-33612214 fax: +91-22-33611020;
OH
OH
OH
Acid catalyst
Chlorobenzene
E-mail: kgap@rediffmail.com
+
a Present Address: 2320 S Brook Street, Department of Chemistry, University
of Louisville, Louisville, KY-40292, USA.
reflux
2
4
3
Entry
Acid catalyst
Yield (%) (4)
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
1
2
3
4
5
p-Toluenesulfonic acid
Methanesulfonic acid
Conc. Sulphuric acid
Tungstate sulfuric acid
Phosphomolybdic acid
86
56
45
35
40
1. (a) S. Patai, in The Chemistry of Quinonoid Compounds, ed. Z.
Rappoport, Wiley, New York, 1988, Vol. 2, Parts 1 and 2. (b) R. H.
Thomson, in Naturally Occuring Quinones IV, Blackie Academic,
London, 1997. (c) R. P. Verma, Anti-Cancer Agents in Med. Chem.,
2006, 6, 489 and references cited therein. (d) S. Spyroudis,
Molecules, 2000, 5, 1291.
2. L. F. Fieser, M. T. Leffler, US Pat., 2 553 648, 1951.
3. R. Bishop, A. Musoke, S. Morzaria, M. Gardner, V. Nene,
Parasitology, 2004, 129, 271.
While considering mechanistic aspect for synthesis of 4, we assume
that the reaction could follow general pathway of acid (p-TSA,
4. (a) M. Mhadhbi, A. Naouach, A. Boumiza, M.-F. Chaabani, S. Ben-
Abderazzak, M.-A. Darghouth, Veterinary Parasitology, 2010, 169,
241.
5. N. McHardy, A. T. Hudson, D. W. Morgan, D. G. Rae, T. T. Dolan,
Research in veterinary science, 1983, 35, 347.
in this case) mediated alkylation of naphthol and might be analogous
to other acid catalysed Friedel-Crafts alkylations.12d,e Cyclohexyl
cation, generated through reaction between cyclohexanol 3 and p-
TSA, would attack 1- naphthol 2 and followed by rearomatisation to
afford 2-cyclohexyl-1-naphthol, 4.
6. A. Erdemir, M. Aktas, N. Dumanli, D. Turgut-Balik, Veterinarni
Medicina, 2012, 57, 559 and references cited therein.
7. L. F. Fieser, US Pat., 2 398 418, 1946.
During screening of reaction sequences for transforming 4 into 1,
reaction conditions developed by Harrity et al13 were testified and
found to provide satisfactory results. Compound 4 was oxidized to 2-
cyclohexyl-1, 4-naphthoquinone 5 by using mild oxidant such as
30% hydrogen peroxide in presence of hydrochloric acid at room
temperature and provided 68% yield of 5. Compound 5 was further
converted into 2-cyclohexyl-(2, 3)-oxirane-1, 4-naphthoquinone, 6
by using 30% hydrogen peroxide in the presence of aq. sodium
carbonate. The reaction was smoothly occurred at room temperature
and provided 76% yield of 6. Isolated epoxide intermediate 6 was
then isomerized by using sulfuric acid at room temperature and
desired product 1 was isolated in good yield of 76% after work up
and purification.
8. E. S. Huyser, B. Amini, J. Org. Chem., 1968, 33, 576.
9. B. S. Khambay, D. Batty, WO Pat., 9 621 354, 1996.
10. H. Britton, D. Catterick, A. N. Dwyer, A. H. Gordon, S. G. Leach,
C. McCormick, C. E. Mountain, A. Simpson, D. R. Stevens, M. W.
J. Urquhart, C. E. Wade, J. Warren, N. F. Wooster, A. Zilliox, Org.
Process Res. Dev., 2012, 16, 1607.
11. (a) C. R. Solorio-Alvarado, C. G. Rodriguez-Cendejas, E. Pena-
Cabrera, ARKIVOC, 2003 (xi), 172. (b) C. R. Solorio-Alvarado, C.
Alvarez-Toledano, E. Peña-Cabrera, ARKIVOC 2004, (i), 64.
12. (a) B. Alberti, Justus Liebigs Annalen der Chemie 1926, 450, 304.
(b) R. P. Perkin, US Pat., 2 125 310, 1936. (c) S. P. Starkov, N. L.
Polyanskaya, N. A. Vozhzhova, G. S. Leonova, Izvestiya Vysshikh
Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya 1977,
20, 1099. (d) T. Nishimura, S. Ohtaka, A. Kimura, E. Hayama, Y.
Haseba, H. Takeuchi, S. Uemura, Applied Catalysis A: General
2000, 194-195, 415. (e) M. Rueping, B. J. Nachtsheim, Beilstein J.
Org. Chem. 2010, 6, No. 6. Published 20 Jan 2010.
13. J. P. A. Harrity, W. J. Kerr, D. Middlemiss, J. S. Scott, J.
Organomet. Chem., 1997, 532, 219.
Conclusion
14. L. F. Fieser, M. Fieser, J. Am. Chem. Soc., 1948, 70, 3177.
The newly developed synthetic route of parvaquone is having
advantages of being operationally simple, environmentally benign
and required cheap and commercially accessible raw materials and
reagents which might contribute effectively toward cost reduction
and making process economically favourable. The intermediates 4, 5
and 6 were obtained in good yields of 86%, 68% and 76%
respectively leading to an overall yield of 33.8%. Use of 30%
hydrogen peroxide, industrially accepted green oxidant, under
control conditions would make the developed process favourable for
scale up when compared with hazardous peroxides under drastic
conditions at inert atmosphere.
Acknowledgements
Pravin C. Patil thankful to TEQIP [Technical Education Quality
Improvement Program] for financial support for this work.
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