U.S. patent application number 10/308651 was filed with the patent office on 2004-06-03 for single pot conversion of artemisinin into arteether.
Invention is credited to Bhakuni, Rajendra Singh, Khanuja, Suman P.S., Singh, Tarun, Tewari, Amit.
Application Number | 20040106809 10/308651 |
Document ID | / |
Family ID | 32392801 |
Filed Date | 2004-06-03 |
United States Patent
Application |
20040106809 |
Kind Code |
A1 |
Bhakuni, Rajendra Singh ; et
al. |
June 3, 2004 |
SINGLE POT CONVERSION OF ARTEMISININ INTO ARTEETHER
Abstract
The present invention provides a method for the preparation of
arteether from artemisinin in one pot in just about 4 hours
comprising reduction of artemisinin into dihydroartemisinin by less
quantity of sodium borohydride in ethanol at room temperature in
the presence of a novel polyhydroxy catalyst, acylation of
dihydroartemisinin in the presence of an acid catalyst, extraction
of arteether from an aqueous reaction mixture using 1% ethyl
acetate in n-hexane followed by workup and purification of the
impure arteether to yield 80-86% (w/w) pure alpha, beta
arteether.
Inventors: |
Bhakuni, Rajendra Singh;
(US) ; Tewari, Amit; (US) ; Singh,
Tarun; (US) ; Khanuja, Suman P.S.;
(US) |
Correspondence
Address: |
TRASK BRITT
P.O. BOX 2550
SALT LAKE CITY
UT
84110
US
|
Family ID: |
32392801 |
Appl. No.: |
10/308651 |
Filed: |
December 2, 2002 |
Current U.S.
Class: |
549/349 |
Current CPC
Class: |
C07D 493/20
20130101 |
Class at
Publication: |
549/349 |
International
Class: |
C07D 307/56 |
Claims
1. A single pot process for the preparation of arteether from
artemisinin comprising the steps of: (a) dissolving artemisinin and
a polyhydroxy catalyst in ethanol at room temperature to obtain a
solution, (b) adding a reducing agent to step (a) solution,
stirring the reaction mixture at a temperature ranging between 20
to 30.degree. C. for about 0.5 to 2 hours to reduce artemisinin
into dihydroartemisinin, (c) adding an acid catalyst to the
reaction mixture of step (b) with cooling, (d) stirring the
reaction mixture of step (c) for about 1 to 2 hours at room
temperature, (e) adding cold water to the reaction mixture of step
(d), extracting with a mixture of ethyl acetate and n-hexane,
separating the organic layer, (f) washing the organic layer of step
(e) with 0.5% aqueous sodium bicarbonate solution followed by
water, (g) drying the washed organic layer of step (f) over
anhydrous sodium sulphate, filtering, evaporating the organic layer
to obtain a residue, and (h) purifying the residue of step (g) by
silica gel column chromatography to obtain arteether.
2. A process as claimed in claim 1, wherein the two reactions,
namely reduction of artemisinin to dihydroartemisinin and
alkylation of dihydroartemisinin into arteether are carried out in
a single pot thereby avoiding the process of isolation of the
intermediate dihydroartemisinin.
3. A process as claimed in claim 1, wherein the time required for
conversion of artemisinin into arteether is about 4 hours.
4. A process as claimed in claim 1, wherein ethanol used acts as a
solvent and an alkylating agent.
5. A process as claimed in claim 1, wherein the polyhydroxy
catalyst is selected from the group consisting of pholoroglucinol,
galactose or dextrose.
6. A process as claimed in claim 1, wherein the ratio of
artemisinin and the polyhydroxy catalyst is in the range of 1:2 to
1:5 w/w.
7. A process as claimed in claim 1, wherein the reducing agent is
selected from the group consisting of sodium borohydride, lithium
aluminium hydride (LiAlH.sub.4), lithium tritert-butoxy aluminium
gydride (Li[OC(CH.sub.3).sub.3].sub.3 AlH), lithium trimethoxy
aluminium hydride (Li(OCH.sub.3).sub.3 AlH), sodium trimethoxy
borohydride (Na(OCH.sub.3).sub.3 BH), sodium bis-2-methoxy, ethoxy
aluminium hydride or a mixture of lithium or sodium in alcohol or
liquid ammonia.
8. A process as claimed in claim 7, wherein the reducing agent is
sodium borohydride.
9. A process as claimed in claim 1, wherein the ratio of
artemisinin and sodium borohydride is in the rage of 1:0.5 to 1:0.7
w/w.
10. A process as claimed in claim 1, wherein the acid catalyst is a
liquid or a solid.
11. A process as claimed in claim 10, wherein the liquid acid
catalyst is a silylated compound.
12. A process as claimed in claim 11, wherein the silylated
compound is chlorotrimethysilane.
13. A process as claimed in claim 12, wherein the w/v ratio of
artemisinin and chlorotrimethysilane is in the range of 1:3 to
1:4.
14. A process as claimed in claim 10, wherein the solid acid
catalyst is an aromatic sulphonic acid.
15. A process as claimed in claim 14, wherein the aromatic
sulphonic acid is p-toluene sulphonic acid.
16. A process as claimed in claim 15, wherein the w/w ratio of
artemisinin and p-toluene sulphonic acid is in the range of 1:3 to
1:4.
17. A process as claimed in claim 1, wherein the acid catalyst is
added to the reaction mixture at a temperature in the range of from
10 to 23.degree. C.
18. A process as claimed in claim 1, wherein the extraction of
crude arteether from aqueous reaction mixture is carried out with a
mixture of 1% ethyl acetate and n-hexane to avoid extraction of
unwanted polar impurities.
19. A process as claimed in claim 18, wherein the extraction of
arteether using the mixture of 1% ethyl acetate and n-hexane may be
performed more than once for complete extraction.
20. A process as claimed in claim 1, wherein column is eluted using
a gradient mixture of hexane-ethyl acetate having the ratio in the
range of 92:8 to 99.5:0.5.
21. A process as claimed in claim 1, wherein 80-86% w/w arteether
is obtained after purification by silica gel chromatography.
22. A process as claimed in claim 1, wherein the arteether obtained
is a mixture of alpha and beta arteether in the w/w ratio range of
20:80 to 30:70.
Description
FIELD OF INVENTION
[0001] The present invention relates to an improved single pot
method for preparation of Arteether from Artemisinin. Arteether
prepared from the process is useful for the treatment of
uncomplicated, severe complicated and multi drug resistant
malaria.
BACKGROUND OF THE INVENTION
[0002] Approximately, out of the 4 billion people suffering from
malaria, 1-3 million people, mostly children die every year
worldwide. The rapidly spreading multidrug resistant parasite to
standard quinoline based antimalarial drugs such as chloroquine and
mefloquine based antimalarial complicate chemotherapy treatment of
malaria patients.
[0003] Artemisinin and its derivative artemether, arteether,
artelinate and artesunate are a class of antimalarials compounds
derived from Artemisia annua which are now proving their promising
activity and are being used for the treatment of uncomplicated
severe complicated/cerebral and multi drug resistant malaria.
Dihydroartemisinin is derived from artemisinin, a sesquiterpene
endoperoxide isolated from the plant Artemisia annua.
[0004] Arteether, a ethyl ether derivative of dihydroartemisinin, a
drug introduced in India for the first time by Central Institute of
Medicinal and Aromatic Plants (CIMAP), Lucknow, has undergone
extensive preclinical, animal, toxicological studies as well as
clinical studies on Indian subjects for drug regulatory purposes.
World Health Organization (WHO) has also recommended arteether as
life saving antimalarial drug. Arteether is more potential as
compared to artemisinin and is an ideal antimalarial drug
especially for treating multi drug resistant and complicated
strains of Plasmodium falciparum. Arteether shows rapid
schizoticial action with quicker clearance rate, short fever
clearance time with no side effects and low recrudescence rate.
[0005] Brossi, et al (Brossi, A; Venugopalan, B; Domingueg, G L;
Yeh,H. J. C; Flippend-Anderson, .J. L.; Buchs, P; Luo, X. D.;
Milhous,W and peters, W; J. Med. Chem. 31, 646-649,1988) reported
the preparation of arteether, the ethyl ether derivative of
dihydroartemisinin in two steps: First artemisinin was reduced with
an excess of sodium borohydride in methanol at 0 to -5.degree. C.
in 3 hours to dihydroartemisinin in 79% yield. In the second step,
arteether is prepared by dissolving the dihydroartemisinin in the
solvent mixture of benzene and ethanol at 45.degree. C. followed by
addition of BF.sub.3 etherate and refluxing the reaction mixture at
70.degree. C. for one hour. After the completion of the reaction it
was worked up, dried over anhydrous sodium sulphate with removal of
the solvent dichloromethane. The reaction yielded arteether along
with some impurities. Column chromatography of the reaction mixture
over silica gel, 1:20 ratio yielded pure alpha and beta arteether
in nearly equal qualitative yield.
[0006] E L-Feraly et al. (E L Feraly, F. S; Al-Yahya M A; Orabi, K.
Y; Mc-Phail D R and Mc Phail A. T. J. Nat. Prod. 55, 878-883, 1992)
reported the preparation of arteether by a process in which
anhydrodihydroartemisinin, prepared from artemisinin was dissolved
in absolute alcohol. The reaction mixture was stirred in the
presence of p-toluene sulphonic acid used as a catalyst. On workup
it yielded a mixture of beta arteether and C-11 epimer in the ratio
of 3:1. In this process only beta arteether is obtained and
separation of C-11 epimer is difficult and preparation of
anhydrodihydroartemisinin is a tedious process. The reaction took
22 hours to complete. The lewis acid catalyst used in this reaction
is required in large amount (60 mg. acid catalyst by 100 mg.
anhydrodihydroartemisinin.
[0007] In another method Bhakuni et al (Bhakuni, R. S.; Jain D. C
and Sharma R. P. Indian. J. Chemistry, 34B, 529-30,1995) arteether,
artemether and other ether derivatives were prepared from
dihydroartemisinin in different alcohol and benzene in the presence
of chlorotrimethylsilane catalyst in 2-4 hours at room temperature.
After workup of the reaction mixture and removal of the solvent,
the impure reaction products were purified over silica gel column
to obtained the pure mixture of alpha, beta ethers.
[0008] Another method is reported by Lin et al. (Lin, A. J. and
Miller, R. E, J.Med Chem. 38,764-770,1995). In this method the new
ether derivatives were prepared by dissolving dihydroartemisinin in
anhydrous ether and appropriate alcohol followed by
BF.sub.3-etherate. The reaction mixture was stirred at room
temperature for 24 hours. The yield of the purified products ranged
from 40-90%. Purification was achieved by the use of silica gel
chromatography.
[0009] Yet another method described by Jain et al (Jain D. C,
Bhakuni R. S, Saxena S, kumar, S and Vishwakarma, R. A. ref: U.S.
Pat. No. 6,346,631, G.B. Application no 0007261.1 and German
application no 10014669.4] teaches preparation of arteether from
artemisinin which comprises: Reduction of artemisinin into
dihydroartemisinin, isolation of dihydroartemisinin, conversion of
dihydroartemisinin by dissolving it in alcohol and adding
trialkylorthoformate in the reaction mixture, which produce ethers
in quantitative yield in 10 hours at 40 degree C.
[0010] The above mentioned methods are not cost effective and are
time consuming. Moreover, benzene, a carcinogenic solvent, used in
the previous methods is not acceptable according to the health
standard. Further, all the above methods require at least two
separate steps to convert artemisinin into ethers i.e reduction of
artemisinin into dihydroartemisinin in the first pot followed by
isolation of dihydroartemisinin and then comes the second step of
conversion of dihydroartemisinin into different ethers in the
second pot.
[0011] The Assignees co-pending U.S. application Ser. No.
10/105,964 filed on Mar. 25, 2002 which is incorporated herein as
prior art reference teaches a process for preparing artemether from
artemisinin. It should be noted that the aforesaid application does
not use a polyhydroxy compound as catalyst during the process of
reduction of artemisinin into dihydroartemisinin. In the present
application, the applicants have utilized a polyhydroxy compound as
a catalyst during the step of reduction of artemisinin to
dihydroartemisinin. The Applicants have been successful in reducing
artemisinin to dihydroartemisinin at room temperature in the
presence of the polyhydroxy compound. It should be noted that to
carry out a reaction not only the reactants play an important role
but also other reaction conditions like solvent used, cooling or
heating, inert atmosphere etc. are also important. Such reaction
conditions provide a particular structure/steriochemistry to the
reactant molecules leading to the desired product. Introduction of
the polyhydroxy compound for the reduction of artemisinin into
dihydroartemisinin provides the ideal environment to the reactant
molecules (artemisinin or the reducing agent or both) to reeact at
room temperature (20-30.degree. C.) which other react only at
temperature in the range of 0-5.degree. C. Also, the Applicants
have found that the extraction of arteether from an aqueous
reaction mixture using 1% ethyl acetate in n-hexane avoids
extraction of unwanted polar impurities as compared to use of
dihydromethane in the co-pending application. Further, the
Applicants have found that resin could not perform esterification
and hence, only unrecoverable catalysts such as
chlorotrimethylsilane and p-toluene sulphonic acid are used in the
present process. Thus the process of the present invention can not
be considered as being obvious to a person of ordinary skill in the
art and present invention provides an efficient method for
conversion of artemisinin to arteether.
OBJECT OF INVENTION
[0012] The object of the present invention is the development of
cost effective and improved single step method for the preparation
of arteether which possesses reduction of artemisinin into
dihydroartemisinin in the presence of a catalyst, conversion of
dihydroartemisinin into arteether followed by extraction of the
same in a single pot.
SUMMARY OF THE INVENTION
[0013] The present invention provides a method for the preparation
of arteether from artemisinin in one pot in just about 4 hours. The
process of the present invention comprises: reduction of
artemisinin into dihydroartemisinin by less quantity of sodium
borohydride in ethanol at room temperature in the presence of a
novel polyhydroxy catalyst, acylation of dihydroartemisinin in the
presence of an acid catalyst followed by extraction of arteether
from an aqueous reaction mixture using 1% ethyl acetate in
n-hexane. Workup of the impure arteether followed by silica gel
column chromatography in 1:5-10 ratio, yields 80-86% (w/w) pure
alpha, beta arteether.
DETAILED DESCRIPITION OF THE INVENTION
[0014] Accordingly, the present invention provides a single step
process for the preparation of arteether from artemisinin in one
pot comprising the steps of:
[0015] a. dissolving artemisinin and a polyhydroxy catalyst in
ethanol at room temperature to obtain a solution,
[0016] b. adding a reducing agent to step (a) solution, stirring
the reaction mixture at a room temperature (20 to 30.degree. C.)
for about 0.5 to 2 hours to reduce artemisinin into
dihydroartemisinin,
[0017] c. adding an acid catalyst to the reaction mixture of step
(b) with cooling,
[0018] d. stirring the reaction mixture of step (c) for about 1 to
2 hours at room temperature,
[0019] e. adding cold water to the reaction mixture of step (d),
extracting with a mixture of ethyl acetate and n-hexane, separating
the organic layer,
[0020] f. washing the organic layer of step (e) with 0.5% aqueous
sodium bicarbonate solution followed by water,
[0021] g. drying the washed organic layer of step (f) over
anhydrous sodium sulphate, filtering, evaporating the organic layer
to obtain a residue, and
[0022] h. purifying the residue thus obtained by silica gel column
chromatography to obtain arteether.
[0023] In an embodiment of the present invention, the two
reactions, namely reduction of artemisinin to dihydroartemisinin
and alkylation of dihydroartemisinin into arteether are carried out
in a single pot thereby avoiding the process of isolation of the
intermediate dihydroartemisinin.
[0024] In another embodiment of the present invention, the time
required for conversion of artemisinin into arteether is about 4
hours.
[0025] In yet another embodiment of the present invention, ethanol
used acts as a solvent and an alkylating agent.
[0026] In still another embodiment of the present invention, the
polyhydroxy catalyst is selected from the group consisting of
pholoroglucinol, galactose or dextrose.
[0027] In a further embodiment of the present invention, the ratio
of artemisinin and the polyhydroxy catalyst is in the range of 1:2
to 1:5 w/w.
[0028] In one more embodiment of the present invention, the
reducing agent is selected from the group consisting of sodium
borohydride, lithium aluminium hydride (LiAIH.sub.4), lithium
tritert-butoxy aluminium gydride (Li[OC(CH.sub.3).sub.3].sub.3
AlH), lithium trimethoxy aluminium hydride (Li(OCH.sub.3).sub.3
AlH), sodium trimethoxy borohydride (Na(OCH.sub.3).sub.3 BH),
sodium bis-2-methoxy, ethoxy aluminium hydride or a mixture of
lithium or sodium in alcohol or liquid ammonia.
[0029] In one another embodiment of the present invention, the
reducing agent is preferably sodium borohydride.
[0030] In an embodiment of the present invention, the ratio of
artemisinin and sodium borohydride is in the rage of 1:0.5 to 1:0.7
w/w.
[0031] In another embodiment of the present invention, the acid
catalyst is a solid or a liquid.
[0032] In yet another embodiment of the present invention, the
liquid acid catalyst is a silylated compound.
[0033] In still another embodiment of the present invention, the
silylated compound is chlorotrimethysilane.
[0034] In one more embodiment of the present invention, the w/v
ratio of artemisinin and chlorotrimethysilane is in the range of
1:3 to 1:4.
[0035] In one another embodiment of the present invention, the
solid acid catalyst is an aromatic sulphonic acid.
[0036] In a further embodiment of the present invention, the
aromatic sulphonic acid is p-toluene sulphonic acid.
[0037] In an embodiment of the present invention, the w/w ratio of
artemisinin and p-toluene sulphonic acid is in the range of 1:3 to
1:4.
[0038] In another embodiment of the present invention, the acid
catalyst is added to the reaction mixture at a temperature in the
range of from 10.degree. to 23.degree. C.
[0039] In yet another embodiment of the present invention, the
extraction of crude arteether from aqueous reaction mixture is
carried out with a mixture of 1% ethyl acetate and n-hexane to
avoid extraction of unwanted polar impurities.
[0040] In still another embodiment of the present invention, the
extraction of arteether using the mixture of 1% ethyl acetate and
n-hexane may be performed more than once for complete
extraction.
[0041] In one more embodiment of the present invention, the column
us eluted using a gradient mixture of hexane-ethyl acetate having
the ratio in the range of 92:8 to 99.5:0.5.
[0042] In one another embodiment of the present invention, 80-86%
w/w arteether is obtained after purification by silica gel
chromatography.
[0043] In a further embodiment of the present invention, the
arteether obtained is a mixture of alpha and beta arteether in the
w/w ratio range of 20:80 to 30:70 w/w.
[0044] In an embodiment of the present invention, the conversion of
artemisinin into pure arteether takes about 6-8 hours which is
significantly less time consuming method.
[0045] In another embodiment of the present invention, the yield of
the final product i.e. pure alpha, beta arteether by 3-10% w/w as
compared to previously reported methods.
[0046] To describe in detail, in the process of invention,
artemisinin and polyhydroxy catalyst were taken in the ratio of 1:2
to 1:5 w/w and dissolved in ethanol at room temperature and stirred
for 5 minutes. Now sodium borohydride is added slowly at the room
temperature (20 to 23.degree. C.) and the reaction mixture is
stirred for about 0.5 to 1.5 hours.
[0047] After completion of the reduction of artemisinin, without
workup or the isolation of the dihydroartemisinin, a solid acid
catalyst, resin or a liquid acid catalyst, chlorotrimethysilane or
trifluroacetic acid is added at 10-20.degree. C. and the reaction
mixture is further stirred for about 1 to 2 hours at room
temperature.
[0048] After completion of the acylation reaction, cooled water is
added to the reaction mixture. The solid catalyst is filtered and
the filtrate or the aqueous reaction mixture extracted with 1%
ethyl acetate in n-hexane. During extraction of the crude
arteethers with 1% ethyl-acetate in hexane, the polyhydroxy
compound remains in the aqueous phase and is discarded since it is
insoluble in hexane-ethyl acetate mixture but soluble in aqueous
phase. The combined ethyl acetate-hexane extract is washed with
0.5% sodium bicarbonate solution followed by water.
[0049] The extract is dried over anhydrous sodium sulphate and
removal of the solvent furnishes impure artemether. Silica gel
column chromatography (1:5 to 10 ratio) with 0.5 to 8% ethyl
acetate in n-hexane furnishes a mixture of alpha and beta
artemether in 80-86% w/w yield.
DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0050] FIG. 1 is a schematic representation of the conversion of
artemisinin into arteether.
[0051] The following examples are given by way of illustration of
the present invention and should not be construed to limit the
scope of the present invention.
EXAMPLE 1
[0052] Artemisinin (1 g.) and polyhydroxy catalyst, dextrose (5 g.)
were stirred in ethanol (20 ml) at room temperature for 5 minutes.
Now sodium borohydride (600 mg) was added slowly for 10 minutes and
the reaction mixture was stirred for about 1 hour at room
temperature (20-23.degree. C.). The reaction was monitored by TLC
to check completion of the reduction step. Acid catalyst
chlorotrimethysilane (3.5 ml) was added slowly at 10-23.degree. C.
and the reaction mixture was further stirred at room temperature
for about 1 hour. Cooled water (about 150 ml) was added to the
reaction mixture the aqueous reaction mixture was extracted with 1%
ethyl acetate in n-hexane (3.times.50 ml).
[0053] The combined ethyl acetate-hexane extract was washed with
0.5% sodium bicarbonate (100 ml) followed by water (50 ml). The
n-hexane extract was dried over anhydrous sodium sulphate and
evaporation of the solvent yielded 1.038 g. of crude arteether
along with some impurities. The impure artemether purified over
silica gel (10 g.) with 0.5 to 8% ethyl acetate in hexane furnished
a mixture of alpha and beta arteether 0.86 g. (86% w/w). Small
portion of arteether was separated by preparative TLC into alpha
and beta isomers and characterized by Co-TLC and spectral
analysis.
EXAMPLE 2
[0054] Artemisinin (1 g.) and polyhydroxy catalyst, dextrose (4 g.)
were stirred in ethanol (15 ml). Sodium borohydride (500 mg.) was
added slowly for 10 minutes and the reaction mixture was stirred
for 30 minutes at room temperature (20-23.degree. C.). After
completion of the reduction step, chlorotrimethysilane (3.5 ml) was
added and the reaction mixture was further stirred for 1.5 hours at
room temperature. After usual work up and purification through
column chromatography (1:5 ratio) a mixture of alpha and beta
arteether (0.805 g., 80.5% w/w) were obtained.
EXAMPLE 3
[0055] Artemisinin (1 g.) and polyhydroxy catalyst, dextrose (2 g.)
were stirred in ethanol (25 ml). Sodium borohydride (700 mg.) was
added slowly for 10 minutes and the reaction mixture was stirred
for 1.5 hours at room temperature (20-23.degree. C.). After
completion of the reduction step, chlorotrimethysilane (4 ml) was
added and the reaction mixture was further stirred for 2 hours at
room temperature (20-23.degree. C.) to give 0.95 g. of crude
arteether. After usual work up and purification through column
chromatography 0.95 g. of crude arteether yielded 0.825 g. of a
mixture of alpha and beta arteether (82.5% w/w).
EXAMPLE 4
[0056] Artemisinin (100 g.) and polyhydroxy catalyst, dextrose (500
mg.) were stirred in ethanol (10 ml) for 5 minutes. Sodium
borohydride (65 mg.) was added slowly to the reaction mixture and
the same was stirred for 1.25 hours at room temperature
(20-23.degree. C.). After completion of the reduction step,
p-toluene sulphonic acid (300 mg.) was added and the reaction
mixture was completed in 4 hours at room temperature. After usual
work up and purification by preparative TLC, the impure reaction
product yielded 53% w/w a mixture of alpha and beta arteether.
EXAMPLE 5
[0057] Artemisinin (100 g.) and polyhydroxy catalyst, galactose
(300 mg.) were stirred in ethanol (5 ml) for 5 minutes. Sodium
borohydride (60 mg.) was added slowly to the reaction mixture and
the same was stirred for 1.5 hours at room temperature
(20-23.degree. C.). After completion of the reduction step, liquid
acid catalyst chlorotrimethysilane (0.35 ml) was added and the
reaction mixture was further stirred for 2 hours to complete the
reaction. After usual work up and purification by preparative TLC,
the impure reaction product afforded 62% w/w of a mixture of alpha
and beta arteether.
EXAMPLE 6
[0058] Artemisinin (100 g.) and polyhydroxy catalyst,
phloroglucinol (400 mg.) were stirred in ethanol. Sodium
borohydride (65 mg.) was added slowly to the reaction mixture and
the same was stirred for 2 hours at room temperature (20-23.degree.
C.). After completion of the reduction step, chlorotrimethysilane
(0.8 ml) was added and the reaction mixture was further stirred for
2 hours at room temperature to complete the reaction. Work up and
purification of the crude product by preparative TLC yielded 74%
w/w a mixture of alpha and beta arteether.
* * * * *