A one-pot conversion of artemisinin to its ether derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01607-6

A one-pot preparation of artemether, arteether and related antimalarial compounds from artemisinin, using NaBH₄/Amberlyst-15, is reported.

Full text of DOI:10.1016/S0040-4039(02)01607-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7235–7237
A one-pot conversion of artemisinin to its ether derivatives†
Chandan Singh* and Pallavi Tiwari
Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
Received 13 May 2002; revised 24 July 2002; accepted 1 August 2002
Abstract—A one-pot preparation of artemether, arteether and related antimalarial compounds from artemisinin, using NaBH4/
Amberlyst-15, is reported. © 2002 Elsevier Science Ltd. All rights reserved.
Artemisinin 1 is the active principle of the Chinese
traditional antimalarial drug Artemisia annua.1 Its semi
synthetic derivatives, such as artemether 3 and arteether
4 are effective against both chloroquine sensitive and
chloroquine resistant P. falciparum and are clinically
used for the treatment of cerebral malaria.2
be exercised during the addition of NaBH4. Further,
this step requires extensive drying of dihydroartemisinin
as only moisture free dihydroartemisinin can be used in
the next step.
In the second step, dihydroartemisinin is reacted with
an appropriate alcohol in the presence of an acid
catalyst such as BF3·Et2O, HCl, Me3SiCl or PTSA.4–7
This step again requires aqueous work-up. Thus, the
conversion of artemisinin to its ether derivatives
requires two independent steps, both of which require
aqueous work-up.
Herein, we report an improved one-pot conversion of
artemisinin to its ether derivatives, which does not
suffer from the above drawbacks. The process consists
of reduction of artemisinin with the NaBH4/Amberlyst-
15 combination to dihydroartemisinin and its in situ
conversion to the desired ether derivative by the addi-
tion of an appropriate alcohol. The product is isolated
by removal of the resin by filtration, concentration of
the filtrate and column chromatography of the crude
product. As the process does not require any aqueous
work-up and is conducted in a single pot, it is well
suited for the industrial synthesis of the ether deriva-
tives of artemisinin.
Compounds 3, 4 and related ether derivatives are cur-
rently prepared in two steps. In the first step
artemisinin is reduced with NaBH4 in MeOH to furnish
dihydroartemisinin 2.3 This step suffers from two major
drawbacks: (i) the reaction conditions are highly basic
which leads to rapid degradation of artemisinin and
dihydroartemisinin, if stringent low temperature condi-
tions (ꢀ0°C) are not maintained, and (ii) NaBH4 reacts
exothermically with MeOH, therefore, great care has to
* Corresponding author. Tel.: +91 0522 212414 PABX-4385; fax: +91 0522 223405; e-mail: chandancdri@yahoo.com
† CDRI Communication No. 6230.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01607-6

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C. Singh, P. Tiwari / Tetrahedron Letters 43 (2002) 7235–7237
Table 1.
Compd
R
Reaction solventa
Reaction time (h)
Yield (%)
3
3
3
4
5
6
7
8
CH3
CH3
CH3
CH2CH3
THF
CH2Cl2
C6H6
72
24
24
72
72
56
4
31
55
32
25
8
80
77
80
55
79
74
65
70
73
70
53
60
56
49
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2CH2CH3
CH2(CH2)3CH3
CH2CHꢀCH2
CH2CH2OH
CH2(CH2)2CH2OH
CH2(CH2)6CH2OH
CH2(CH2)8CH2OH
CH2(CH2)10CH2OH
CH2(CH2)14CH3
p-CH2C6H4-COOCH3
9
10
11
12
13
14
7
18
a After reduction in THF, THF was removed under reduced pressure and replaced with CH2Cl2 or C6H6.
In a typical experiment, NaBH4 (0.1 g) was added over
5 min to a stirred mixture of artemisinin (0.2 g) and
Amberlyst-15 (1.0 g) in THF (20 ml) and the reaction
was stirred at room temperature for 30 min. MeOH (2
ml) was added and the reaction mixture was stirred at
rt for a further 72 h. The resin was removed by
filtration, the filtrate was concentrated and the crude
product chromatographed to give 0.17 g (80% yield) of
artemether as a mixture of a- and b-isomers isolated in
the ratio8 1:3. The etherification step was faster when
after the reduction step, THF was removed under
reduced pressure and replaced by CH2Cl2 or benzene.
Several ethers were prepared using this procedure in
53–82% yields (Table 1).9,11
Shen, C. C. Med. Res. Rev. 1987, 7, 29; (c) Zaman, S. S.;
Sharma, R. P. Heterocycles 1991, 32, 1593; (d) Butler, A.
R.; Wu, Y. L. Chem. Soc. Rev. 1993, 21, 85; (e) Mesh-
nick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S.
Microbiol. Rev. 1996, 60, 301; (f) Haynes, R. K.; Von-
willer, S. C. Acc. Chem. Res. 1997, 73; (g) Bhattacharya,
A. K.; Sharma, R. P. Heterocycles 1999, 51, 1681.
2. For the current status of artemisinin derivatives in the
treatment of malaria, see: Asthana, O. P.; Srivastava, J.
S.; Valecha, N. J. Parasitic Diseases 1997, 21, 1 and
references cited therein.
3. Brossi, A.; Venogopalan, B.; Domniquez, G. L.; Yeh, H.
J. C.; Flippen, A. J. L.; Buchs, P.; Luo, X. D.; Milhous,
W. J. Med. Chem. 1988, 31, 646.
4. Lin, A. J.; Klayman, D. L.; Milhous, W. K. J. Med.
Chem. 1987, 30, 2147.
5. Yun, R. J. Drugs Future 1982, VII, 716.
6. Bhakuni, R. S.; Jain, D. C.; Sharma, R. P. Ind. J. Chem.
1995, 34B, 529.
7. El-Feraly, F. S.; Al-Vahya, M. A.; Oribi, K. V.; McPhail,
D. R.; McPhail, A. T. J. Nat. Prod. 1992, 55, 878.
8. Ratio of a- and b-isomers was calculated on the basis of
1H NMR.
Alternatively, the reaction can be stopped after the
reduction step. In this case, simple filtration followed
by the concentration of the filtrate and chromato-
graphic purification of the crude product furnishes
dihydroartemisinin in acceptable yields. The reaction
was very slow when Amberlite 120 instead of
Amberlyst-15 was used. Of the several solvents used
(THF, DME, 1,4-dioxan, etc.), THF gave the best
results. The resin could be recovered, regenerated and
reused without loss of activity.
9. Preparation of compounds 5–6 and 9–14 has been
reported earlier.1b,10
10. Kanchan, R. Ph.D. Thesis, Poorvanchal University,
Jaunpur, India, 1999.
Thus, we have developed a one-pot process suitable for
the industrial synthesis of ether derivatives of dihy-
droartemisinin. Absence of aqueous work-up and recy-
cling of the acid catalyst are special features of the
process.
11. Selected spectral data: a-Artemether 3 [1H NMR (200
MHz, CDCl3): l 0.88 (d, 3H, J=7.1 Hz, CH3), 0.96 (d,
3H, J=5.6 Hz, CH3), 1.45 (s, 3H, CH3), 3.51 (s, 3H,
OCH3), 4.35 (d, 1H, J=9.2 Hz, C-10), 5.30 (s, 1H, C-12);
FABMS: m/z 299 (M++H), 267 (M+−OCH3)] and b-
artemether 3 [1H NMR (200 MHz, CDCl3): l 0.90 (d,
3H, J=7.2 Hz, CH3), 0.95 (d, 3H, J=6 Hz, CH3), 1.44
(s, 3H, CH3), 3.42 (s, 3H, OCH3), 4.67 (d, 1H, J=3.3 Hz,
C-10), 5.38 (s, 1H, C-12); FABMS: m/z 299 (M++H), 267
(M+−OCH3)].
Acknowledgements
Pallavi Tiwari wishes to thank the Council of Scientific
and Industrial Research, New Delhi, for the financial
assistance in the form of a senior research fellowship.
a-Hydroxy ethyl ether derivative of dihydroartemisinin 8
[1H NMR (200 MHz, CDCl3): l 0.91 (d, 3H, J=7.2 Hz,
CH3), 0.96 (d, 3H, J=5.7 Hz, CH3), 1.42 (s, 3H, CH3),
3.74 (m, 2H), 3.85 (m, 2H), 4.47 (d, 1H, J=9.2 Hz,
C-10), 5.37 (s, 1H, C-12); FABMS: m/z 329 (M++H), 311
(M+−OH), 267 (M+−OCH2CH2OH)] and b-hydroxy ethyl
References
1. For reviews on artemisinin and its derivatives, see: (a)
Klayman, D. L. Science 1985, 228, 1049; (b) Luo, X. D.;

C. Singh, P. Tiwari / Tetrahedron Letters 43 (2002) 7235–7237
7237
ether derivative of dihydroartemisinin 8 [1H NMR (200
MHz, CDCl3): l 0.89 (d, 3H, J=7.6 Hz, CH3), 0.95 (d,
3H, J=5.7 Hz, CH3), 1.43 (s, 3H, CH3), 3.73 (m, 4H,
−OCH2
(2×d, 2×2H, J=8.3 Hz, aromatic protons); FABMS: m/z
433 (M++H), 267 (M+−OCH2
C6H4COOCH3)] and b-p-
carbomethoxy benzyl ether derivative of dihy-
droartemisinin 14 [1H NMR (200 MHz, CDCl3): l 0.93
(d, 3H, J=7 Hz, CH3), 0.97 (d, 3H, J=4.4 Hz, CH3),
1.45 (s, 3H, CH3), 3.91 (s, 3H, CH3), 4.57(d, 1H, J=13.3
6 C6H4COOCH3), 5.34 (s, 1H, C-12) 7.43 and 8.00
6
OCH6 2CH6 2OH), 4.84 (d, 1H, J=3.3 Hz, C-10), 5.44 (s,
1H, C-12); FABMS: m/z 329 (M++H), 311 (M+−OH),
267 (M+−OCH2CH2OH)].
a-p-Carbomethoxy benzyl ether derivative of dihy-
droartemisinin 14 [1H NMR (200 MHz, CDCl3): l 0.93
(d, 3H, J=7 Hz, CH3), 0.98 (d, 3H, J=7.9 Hz, CH3),
1.46 (s, 3H, CH3), 3.91 (s, 3H, CH3), 4.51(d, 1H,
J=9.3 Hz, C-10), 4.68 (d, 1H, J=13.3 Hz,
Hz, −OCH
10), 4.95 (d, 1H, J=13.3 Hz, −OCH
6
2C6H4COOCH3), 4.91 (d, 1H, J=3.3 Hz, C-
2C6H4COOCH3),
6
5.45 (s, 1H, C-12), 7.38 and 7.97 (2×d, 2×2H, J=8.3 Hz,
aromatic protons); FABMS: m/z 433 (M++H), 267 (M+−
OCH6 2C6H4COOCH3)].
−OCH6 2C6H4COOCH3), 5.03 (d, 1H, J=13.3 Hz,