One-pot green synthesis of β-artemether/arteether

Article abstract of DOI:10.1039/c4ra05531d

An efficient one pot green synthesis of β-artemether/arteether from artemisinin has been developed using a sodium borohydride-cellulose sulfuric acid (CellSA) catalyst system. The green methodology is high yielding and the catalyst has good recyclability.

Full text of DOI:10.1039/c4ra05531d

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One-pot green synthesis of b-artemether/
arteether†
Cite this: RSC Adv., 2014, 4, 31973
*
Atul Kumar and Ajay Kumar Bishnoi
Received 6th May 2014
Accepted 25th June 2014
DOI: 10.1039/c4ra05531d
www.rsc.org/advances
An efficient one pot green synthesis of b-artemether/arteether from and Riamet, Falcynate-LF) and is a rst-line treatment for
artemisinin has been developed using a sodium borohydride-cellulose uncomplicated Plasmodium falciparum malaria in most malaria-
sulfuric acid (CellSA) catalyst system. The green methodology is high endemic countries.3
yielding and the catalyst has good recyclability.
Over the last decade, extensive synthetic efforts have been
directed towards the development of synthesis for artemether/
arteether. The synthesis of artemether/arteether from artemisinin
involves two steps. First step involves the reduction of carbonyl
group and in the second step etherication take place. These
reported methodologies produce good yields but have some
limitations such as a the carcinogenic solvents like benzene, use
of highly hazardous Lewis acid and pro acid, use of column
chromatograph in the separation of desired b-isomer and two step
synthesis (Fig. 2). Lewis acid such as BF3$Et2O, Me3SiCl has the
additional drawback of moisture sensitivity (Fig. 2).
Hence, the development of simple, and environmentally
benign and sustainable resources protocol for the synthesis of
artemether/arteether in high purity and yield with minimal side
product formation such as anhydroartemisinin, 9-epi-arte-
mether (a + b) is highly desirable.
In this context, we wish to report here one-pot, environment
friendly and cost effective process for preparation of methyl/
ethyl ether derivative of artemisinin. The process consists of
reduction of artemisinin to dihydroartemisinin and its in situ
conversion to the desired ether derivative by the addition of an
appropriate alcohol catalysed by combination of NaBH4/cellu-
lose sulfuric acid (CellSA). The cellulose sulfuric acid is a
natural biodegradable solid support acid catalyst,4 which effi-
ciently promote the acid-catalyzed reactions and has cost
effectively and good recyclability (Scheme 1).
Introduction
Malaria is a major tropical parasitic disease affecting 500 million
people worldwide and causing the death of 1–2 million people
per year, mostly children in Africa.1 Plasmodium is the causative
agent of malaria; the most dangerous species is Plasmodium
falciparum, which is responsible for malaria complications such
as cerebral malaria. Artemisinin is a naturally occurring
sesquiterpene lactone of prominent value in the pharmacolog-
ical treatment of human malaria. Artemisinin and its derivatives
(dihydroartemisinin, artemether, artesunate) are essential to
modern malaria therapy, thus requiring an efficient synthetic
route for these compounds (Fig. 1).2 Recently, the World Health
Organization (WHO) has approved artemisinin combination
therapy (ACT) containing artemether–lumefantrine (Coartem
Fig. 1 Artemisinin and its clinically useful derivatives.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow, 226031, India. E-mail: dratulsax@gmail.com; Fax: +91-522-26234051;
Tel: +91-522-2612411
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
Fig. 2 Conventional approaches for synthesis of artemether from
of b-artemether/b-arteether and other details. See DOI: 10.1039/c4ra05531d
artemisinin.
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trialkylorthoacetate was claimed to allow use of a lower amount
of acid and to increase the reaction rate with high selectivity of
b-arteether.15 The reaction was monitored by TLC and HPLC to
check completion of the reaction. The cellulose sulfuric acid
was removed by ltration, the ltrate was concentrated. Then
we added a solution of sodium bicarbonate to terminate the
reaction. The reaction mixture was vacuum evaporated to
dryness. As simple ltration is enough to remove the catalyst
and hence quench the reaction rather than the generally used
aqueous workup, the protocol may nd application in large-
scale synthesis of artemether/arteether. Aerwards water was
added to reaction mixture below 20 ꢀC to precipitate out the
crude arteether. The reaction mass was ltered and washed with
Scheme 1 One-pot conversion of b-artemisinin to artemether.
Industries prefer reaction protocols that give the product just
by ltration with no aqueous workup using hazardous organic
solvents. The synthesis of artemether from artemisinin basi-
cally have reduction and etherication steps.5 Reductions step
are ubiquitous in artemisinin to dihydroartemisinin due to
their synthetic utility and high selectivity. Sodium borohydride
(NaBH4) is used as reducing agent, followed by a multistep
workup procedure. Diisobutylaluminium hydride (DIBAL-H) is
another reducing agent, requiring dryꢀ dichloromethane as
solvent, lower reaction temperature À78 C and with a smaller
yield than NaBH4.6
ꢀ
ethanol. The reaction mass was heated to 40 Æ 5 C in water.
The reaction mass was seeded with pure b-arteether. Then it was
ltered, washed with chilled 50% solution of ethanol in water
and suck dried. By above recrystallization method which
removed the side product impurities such as anhy-
droartemisinin, 9-epi-arteether (a + b).16 A pure b-arteether
obtained by crystallization method as given above and charac-
terized by chromatogram of HPLC.
Recently, J. M. Williams et al. demonstrated a continuous ow
chemistry protocol for stoichiometric reductions of artemisinin
to dihydroartemisinin.7 There are several methods are reported
by using acid catalysts such as sulphuric acid,8 phosphoric acid,
anhydrous hydrochloric acid,9 p-toluenesulfonic acid,10
BF3$Et2O,11 Me3SiCl,12 AlCl3, or a cation exchange resin13 and pro
acid14 like acetyl chloride, methane sulphonyl chloride, thionyl
chloride etc. for the preparation ether derivative of artemisinin.
The effort has been also focused to minimise the amount of acid
catalysts and with the used of trialkyl orthoformate as a cosol-
vent. All these methodologies require use of hazardous reaction
conditions in terms of solvent and catalysts. In this context the
present report demonstrates the reduction of artemisinin and
subsequent etherication in one pot in the presence of a catalytic
amount of cellulose sulfuric acid (CellSA) to achieve good yields
with excellent diastereoselectivity (b/a, 5 : 1).
Reduction of artemisinin with LiBHEt3
To examine and explore the of the solid support acid catalyst,
cellulose sulfuric acid along with other reducing agent such as
LiBHEt3. Of interest, we found the good yield of arteether with
LiBHEt3/CellSA. Artemisinin was dissolved in dry THF and then
cellulose sulfuric acid (0.015 g), trimethylorthoacetate (0.5 ml),
EtOH (15 ml) was added and maintain the temperature to 0 ꢀC
for 60 min along with slow addition of LiBHEt3 solution (1 M in
THF). Aer that reaction mixture was stirred at room tempera-
ture for a further 90 min. and work up with same methodology
as mentioned above. The reaction took almost the same time
and less yield than NaBH4 when LiBHEt3 use as reducing agent.
HPLC was carried out on a C18 column (250 mm, 4 mm, and
5 mm) (Merck). The injection volume was 20 ml and the column
effluent was monitored at 215 nm. The mobile phase consisted
of acetonitrile and water, at a ow rate of 1 ml minÀ1. The
optimized mobile phase was composed of 70% acetonitrile and
30% water. The detection was performed at 216 nm and the
injection volume was 20 ml (Fig. 4 and 5).
Result and discussion
Reduction of artemisinin with NaBH4
We began our study to screen the optimal reaction conditions
for the synthesis of arteether from artemisinin. We rst exam-
ined method for the preparation of arteether from artemisinin
in one pot in just about 2.5 hours. In an experiment, NaBH4
(67 mg, 1.77 mmol, 2.5 equ.) was added over 10 min to a stirred
mixture of artemisinin (200 mg, 0.71 mmol) and cellulose
sulfuric acid (0.015 g), trimethylorthoacetate (0.5 ml), in EtOH
(15 ml) and the solution was stirred at À5 to 0 ꢀC for 60 min, and
then stirred at room temperature for 1.5 h. During the investi-
gations different amounts of NaBH4 were tested in order to nd
the smallest necessary amount for the best yield. Here, we were
used 1.5, 2.0, 2.5 and 3.0 equivalent of NaBH4 as reducing agent
in reaction media. Notably, we observed that 2.5 equ. of NaBH4
was efficient amount for better yield. The reaction solvent
consisted of the respective alcohol supplemented with the cor-
The catalyst loading was optimized by synthesis of arteether
as an model reaction. Reaction took place in 2.5 h with 0.015 g
of catalyst loading and almost 82% yield was obtained.
responding trialkyl orthoacetate. The use of cosolvent such as Fig. 3 Catalyst optimization plot and reusability.
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chromatography, Merck) in 20 ml of n-hexane, 1.0 g of chlor-
ꢀ
osulfonic acid (9 mmol) was added dropwise at 0 C over 2 h.
HCl gas was removed from the reaction vessel immediately.
Aer the addition was complete, the mixture was stirred for 2 h.
Then, the mixture was ltered, washed with 30 ml of acetoni-
trile, and dried at room temperature to obtain 5.47 g cellulose
sulfuric acid as a white powder.17
Fig. 4 HPLC chromatograms of b-artether.
General procedure for the arteether from artemisinin in one-
pot
To a solution of artemisinin (200 mg, 0.71 mmol) in ethanol
(15 ml) and trimethyl orthoacetate (0.5 ml) was added NaBH4
(67 mg, 1.77 mmol, 2.5 equ.) and cellulose sulfuric acid (0.015
ꢀ
g). Reaction mixture was carried out at À5 to 0 C for 60 min,
and then stirred at room temperature for 1.5 h. Then we added a
solution of sodium bicarbonate to quenched the reaction. The
slurry was stirred in an below 20 ꢀC for 1 h and allowed to settle
for 30 min. Solid crude arteether was collected by ltration, and
the cake was washed with of ethanol. The reaction mass was
Fig. 5 HPLC chromatograms of reaction after 2.5 h (a) a-artether and heated to 40 Æ 5 ꢀC in water. The reaction mass was seeded with
(b) b-artether.
pure b-arteether. Then it was ltered, washed with chilled 50%
solution of ethanol in water and dried.
Lowering the catalyst loading to 0.005–0.01 g results in 75–78%
General procedure for the artemether from artemisinin in
yield of arteether with a longer reaction time of more than 2.5 h,
one-pot
whereas increasing the concentration of catalyst has no signif-
Artemisinin (200 mg, 0.71 mmol) in methanol (15 ml) and tri-
methylorthoformate (0.5 ml), cellulose sulfuric acid (0.015 g),
icant effect on the yield of the reaction. Thus our present study
enabled us to nd the efficient amount of catalyst which is
summarized in Fig. 3.
ꢀ
was carried out at À5 to 0 C for 60 min, and then stirred at
room temperature for 1.5 h. The reaction was monitored by TLC
and HPLC to check completion of the reaction. The cellulose
sulfuric acid was removed by ltration, the ltrate was
concentrated. Then we added a solution of sodium bicarbonate
to terminate the reaction. Then, follow above recrystallization
method.
Reusability of solid acid catalyst is address the green meth-
odology of the reaction. Reusability of catalyst was observed
under same reaction condition as given above, that is, synthesis
of arteether. Aer completion of reaction, cellulose sulfuric acid
was recovered from the reaction mixture by simple ltration,
washed properly with acetone, and dried in oven for 3 h at 70 ꢀC
prior to its use in the absence of fresh catalyst. It was noticed
that catalyst exhibited quite good reusability at least four addi-
tional times in subsequent reactions under the same reaction
conditions without any remarkable loss in productivity (Fig. 3).
Acknowledgements
A.K.B. is thankful to CSIR-SRF New Delhi for nancial support.
The authors also acknowledge the analytical facilities of CSIR-
CDRI. Financial support from CSIR-Network project BSC-0104.
The CSIR-CDRI Communication No. is 8732.
Conclusion
In summary, we have developed a green one pot synthetic
methodology for the synthesis b-artemether/arteether using
sodiumborohydride and cellulose sulfuric acid a natural
carbohydrate solid acid catalyst system.
This process requires no column chromatography with
simple work-up, and it generates less hazardous waste. The
developed methodology is efficient, cost-effective and the cata-
lyst used is eco-friendly, reusable, and biodegradable.
Notes and references
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Experimental section
Representative procedure for catalyst preparation
Preparation of cellulose sulfuric acid. To a magnetically
stirred mixture of 5.00 g of cellulose (DEAE for column
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