The present invention relates to a simple process for the recovery of dihydroartemesinin, a useful intermediate for the preparation of ether derivatives of dihydroartemisinin, which are well-known antimalarial agents.
Dihydroartemisinin is derived from artemisinin, which is a sesquiterpene lactone isolated from Chinese-Vietnamese plant Artemesia annua L. Of the ether derivatives of dihydroartemisinin represented by Formula I,
(Formula Removed )
Formula I
wherein R can be alkyl, aryl or aralkyl, the ß-alkyl ether derivatives viz., artemether of Formula I (A) and arteether of Formula I(B) have been extensively studied and found to be effective in the treatment of malaria including umcomplicated/severely complicated/cerebral and multi-drug resistant malaria
(Formula Removed )


Formula I(A)

Formula I(B)

Coartem® (Artemether + Lumefantrine), a fixed dose combination of two active ingredients, artemether and lumefantrine (a synthetic racemic fluorene derivative) is indicated in artemisinin-based combination therapy (ACT) used to treat malaria including the stand by-emerging treatment of adults and children with infections due to P. falciparum or mixed infections including P. falciparum-the deadliest form of the disease. The combination has gametocytocidal action.
P.falciparum and p.virax are the two dominant species with relative frequency of 60% and 40% respectively. However, this proportion varies from place to place and from season to season. In

malaria epidemic situations, P. falciparum is the dominant parasite species and almost all malarial deaths happen due to infections by this species. Moreover, the biological diversity of P. falciparum, its ability to develop resistance to a number of anti-malarial drugs has been a major challenge in malaria treatment.
Several processes are reported for the preparation of Artemether from dihydroartemesinin which basically involves reaction of dihydroartemesinin with an etherifying agent. The dihydroartemesinin starting material is obtained by reduction of artemesinin, which is a naturally occurring sesquiterpene. The reported processes suffer from low yield and purity of dihydroartemesinin and artemether and require additional purification by chromatographic techniques
Our co-pending Indian Patent Application No. 13/DEL/2007 discloses a simple and cost-effective process for the preparation of pure artemether without employing any chromatographic
purification.
The present inventors, in an effort to develop a more efficient process for preparation of artemether, have surprisingly found that substantial amounts of dihydroartemesinin can be recovered from the mother liquor of artemether. The dihydroartemesinin thus obtained is of good purity and can be directly employed in the preparation of artemether. The recovery and recycling of dihydroartemesinin by the present process enables preparation of artemether of purity >99.5%.
A first aspect of the present invention provides a process for the recovery of dihydroartemisinin
of Formula II,
(Formula Removed )
Formula II
wherein the said process comprises of,
a) heating an aqueous mixture comprising the mother liquor of artemether
b) cooling the mixture of step a)

c) isolating the solid obtained in step b)
d) treating the solid obtained in step c) with an acid in an aqueous solvent
e) isolating dihydroartemesinin from the reaction mass thereof.
Artemether can be prepared by methods known in the art. To the mother liquor obtained after isolation of artemether, deionized water is added and the aqueous mixture heated to about 30-50°C for 0.5-1 hour. The mixture is then cooled to 5-15°C and stirred for 2 hours. The solid product is filtered, washed with deionized water and dried at about 30-45°C. The solid product so obtained is a mixture of artemether (a and p isomers) and anhydrodihydroartemesinin.
To the crude solid product obtained above, an aqueous solvent is added and the mixture stirred at about 30-45°C and then cooled to about 15-25°C. To the cooled mixture an acid is added. The reaction mixture is stirred at about 20-35°C for about 5-10 hours. The reaction progress is monitored by High Performance Liquid Chromatography (HPLC). After completion of the reaction, the mixture is cooled to about 0-10°C and deionized water is added while stirring at 0-10oC The mixture is stirred for 2-4 hours at 0-10°C. The product so obtained is filtered, washed and dried to obtain dihydroartemesinin.
Dihydroartemesinin recovered by the present process can be directly converted to the ether derivative thereof represented by Formula I, by methods known in the art without any further purification. The conversion of dihydroartemesinin to artemether can be carried out as
exemplified in the example.
The term "aqueous solvent" as used herein implies a mixture of water and one or more organic solvent(s). Suitable organic solvents can be selected from acetic acid, formic acid and the like or
mixtures thereof.
Suitable acid can be selected from the group comprising of organic and inorganic acids or mixtures thereof Inorganic acids can be selected from the group comprising of perchloric acid hydrobromic acid, hydroiodic acid and the like or mixtures thereof. Organic acids can be selected from the group comprising of trifluoroacetic acid, methanesulphonic acid, p-toluenesulphonic acid and the like or mixtures thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of dihydroartemisinin
Step a) Isolation of crude solid product from the mother liquor of artemether
To the mother liqyor of artemether (600 ml) was added deionized water (600 ml) 25°C. The mixture was first heated to 35-40°C and stirred at for 0.5 hours and then was cooled to 5-10°C and stirred for 2 hours. The product so obtained was filtered, washed with deionized water (50 ml) and dried to afford the title compound which is a mixture of a-Artemether, (3-Artemether and anhydro-dihydroartemesinin. Yield 15 g (16.7%)
Step b) Recovering dihydroartemisinin from the crude solid product obtained in step a)
To a mixture of acetic acid (105 ml) in water (70 ml) was added the crude solid obtained in step a) (35 g) at 35-40°C to get a clear solution. The mixture was stirred and cooled to 20-25°C and 70 % perchloric acid (5.25 ml) was added. The reaction mixture was stirred at 25-30°C for 7 hours and the reaction progress was monitored by High Performance Liquid Chromatography (HPLC). After completion of the reaction, the mixture was cooled to 0-5°C and deionized water (700 ml) was added slowly under stirring at 0-5°C. The resultant mixture was stirred at 0-5°C for 2 hours. The product so obtain was filtered, washed with deionized water (105 ml), methanol (70 ml) and dried at 35-40°C till moisture content was not more than 2% to afford the title compound. Yield- 16.1 g (48%) Purity 98.7% (sum of two isomers) (by HPLC)
Preparation of artemether from recovered dihydroartemesinin
To a stirred mixture of dihydroartemisinin (25 g) in trimethyl orthoformate (75ml) at 5-10°C was added water (3.75 ml) and p-toluenesulphonic acid (1.25 g). The reaction progress was monitored by High Performance Liquid Chromatography. After completion of the reaction, the mixture was quenched with aqueous sodium bicarbonate solution (5%). The quenched mixture was extracted with dichloromethane. The dichloromethane layer was treated with activated carbon and the thus treated organic layer was filtered over hyflo. The filtrate was concentrated under vacuum and the traces of dichloromethane were removed using methanol under vacuum till the residual volume was 75 ml. To the concentrated mixture water (37.5ml) was added drop-wise at 20-30°C and the resultant mixture was stirred for 1 hour. The solid so obtained was filtered, washed with aqueous methanol (50%) and dried to afford the title compound as a white crystalline powder. Yield 20 g (80 %) Purity. 99.02% (by HPLC)
Purification of p-Artemether
Crude artemether (18 g) was dissolved in n-Hexane (54 ml) at 30-35°C. The solution so obtained was gradually cooled to -10°C over 5 hour at the rate of 10°C per hour and finally cooled to -10 to -12°C and stirred at for 2 hours. The cooled solution was filtered and dried to afford the title compound as a white crystalline powder.
Yield 13.5(75%) Purity: 99.80% (by HPLC)

WE CLAIM:
1 A process for the recovery of dihydroartemisinin of Formula II,
(Formula Removed)
Formula II
wherein the said process comprises of,
a) heating an aqueous mixture comprising the mother liquor of artemether
b) cooling the mixture of step a)
c) isolating the solid obtained in step b)
d) treating the solid obtained in step c) with an acid in an aqueous solvent,
e) isolating dihydroartemesinin from the reaction mass thereof.
2. The process according to claim 1 wherein the aqueous solvent is a mixture of water and an organic solvent.
3 The process according to claim 2 wherein the organic solvent is selected from the group
comprising of acetic acid, formic acid or mixtures thereof.
4 The process according to claim 3 wherein the organic solvent is acetic acid.
5 The process according to claim 1 wherein the acid is selected from the group comprising of
organic and inorganic acids or mixtures thereof.
6 The process according to claim 5 wherein the organic acid is selected from the group
comprising of TFA, CH3SO3H and p-TSA or mixtures thereof.
7 The process according to claim 5 wherein the inorganic acid is selected from the group
comprising of perchloric acid, HBr, HI or mixtures thereof.
8. The process according to claim 7 wherein the inorganic acid is perchloric acid.
9. A process for preparation of ether derivative of dihydroartemisinin of Formula I,
(Formula Removed)
Formula I
wherein R is alkyl, aryl or aralkyl and wherein the said process comprises of,
a) recovering dihydroartemesinin by the process of claim 1,
b) reacting dihydroartemesinin with an etherifying agent,
c) isolating the ether derivative of dihydroartemisinin of Formula I from the reaction mass
thereof.
10 The process according to claim 9 wherein R is methyl.