NARKHEDE, Sachin (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
PEDGAONKAR, Yogesh (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
CHAVAN, Sunil (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
SHARMA, Mahendra Kumar (Mahyco Research Center, Village Dawalwadi Badnapur,Jalna-Aurangabad Road, Jalna 3, 431 20, IN)
DEGANI, Mariam (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
NARKHEDE, Sachin (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
PEDGAONKAR, Yogesh (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
CHAVAN, Sunil (Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of Mumbai, Nathalal Parekh Marg, Matunga 9 Mumbai, 400 01, IN)
SHARMA, Mahendra Kumar (Mahyco Research Center, Village Dawalwadi Badnapur,Jalna-Aurangabad Road, Jalna 3, 431 20, IN)
We claim:
1. A process for preparing ester derivative of artemisinin, said process comprising of:
(a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound in a solvent mixture consisting of an aprotic solvent and a C 3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes;
(b) esterifying the dihydroartemisinin in presence of succinic anhydride and imidazole or its derivative in an aprotic solvent at a temperature in the range of 20°C to 35°C for 10 to 210 minutes to get a crude product; and
(c) isolating the ester derivative of artemisinin by crystallisation from crude product.
2. The process as claimed in claim 1, wherein ratio of artemisinin to sodium borohydride is in the range of 1 :0.1 to 1 :0.5 w/w. 3. The process as claimed in claim 1, wherein the dihydroxy compound is a C 2 -C 3 diol selected from a group consisting of ethanediol, 1 ,2-propanediol and mixtures thereof.
4. The process as claimed in claim 1, wherein ratio of artemisinin to dihydroxy compound is in the range of 1 :0.2 to 1 : 1 w/w. 5. The process as claimed in claim 1, wherein the aprotic solvent used for the reduction is selected from a group consisting of chloroform, dichloromethane, toluene, ethyl acetate and hexane.
6. The process as claimed in claim 1, wherein the C 3 alcohol is either isopropanol or n-propanol. 7. The process as claimed in claim 1, wherein reduction is carried out at a temperature range of 15 to 20°C in 20 to 25 minutes.
8. The process as claimed in claim 1, wherein the imidazole derivative is N-(Ci-C 3 ) alkylimidazole.
9. The process as claimed in claim 1, wherein the imidazole derivative is N- methylimidazole. 10. The process as claimed in claim 1, wherein the imidazole derivative is selected from a group consisting of 4-methylimidazole and 5-methylimidazole.
11. The process as claimed in claim 1 , wherein the aprotic solvent used for esterification is selected from a group consisting of chloroform, tetrahydrofuran, dichloromethane, acetonitrile, and 1 ,4-dioxane. 12. The process as claimed in claim 1 wherein the esterification is carried out at a temperature range of 25 to 35°C in 25 to 210 minutes.
13. The process as claimed in claim 1, wherein ratio of artemisinin to imidazole or its derivatives is in the range of 1 : 0.1 to 1 : 0.5w/w.
14. The process as claimed in claim 1, wherein the crystallization is done using the mixture of water and methanol or ethanol or acetone. |
PREPARATIVE PROCESS FOR ARTESUNATE FROM ARTEMISININ
This application claims priority from Indian Provisional specification number 122/MUM/2007 dated 19 January 2007 and 32/MUM/2008 dated 4 January, 2008.
FIELD OF INVENTION The present disclosure relates to a process for preparation of artesunate, 10a- hemisuccinate of dihydroartemisinin, from artemisinin involving reduction of artemisinin to dihydroartemisinin followed by its esterification. Artesunate and aretsunic acid are customary names of dihydroartemisinin hemisuccinate.
BACKGROUND OF THE INVENTION Artemisinin and its ether and ester derivatives show antimalarial activity against multidrug resistant strains. Ether derivatives like arteether and artemether shows better activity but they suffer from some limitation like solubility, short half life. Unlike ether derivatives, ester derivatives like artesunate has increased solubility and improved pharmacokinetic properties. The water insoluble dihydroartimisinin hemisuccinate is given orally in tablet form and water soluble artesunate sodium is given as LV.
Artesunate was first prepared by Chinese scientists, using different methods. One of them describes acylation of dihydroartemisinin by succinic anhydride in pyridine at 30 0 C for 24 hr with yield of 60%. In another method, described in Acta. Chim. Sinica 40(6), 557-561., ester derivatives of dihydroartemisinin was prepared in presence of 4- (N, N-dimethylamino) pyridine and triethylamine as basic catalyst and 1 ,2 dichloroethane as solvent. The reaction is continued until complete conversion of dihydroartemisinin and product is isolated and purified by silica gel column giving overall yield 60-90%.
Another improved method disclosed in US patent 5654446, describes preparation of artesunate from dihydroartemisinin and succinic anhydride in presence of triethylamine as basic catalyst and in low boiling water miscible dry solvent like acetone. After completion of reaction, mixture is acidified and diluted with water to get artesunate. The yield of esterification is 96%.
U.S. patent 6677463 discloses one pot method for preparation of artesunate from artemisinin. Method describes reduction of artermisinin to dihydroartemisinin in presence
of polyhydroxy compound and sodium borohydride. After completion of reaction succinic anhydride and anion exchange resin was added to reaction mass and stirred for 2 hrs. Then cold water was added and product was extracted with ethylacetate hexane mixture in pH range of 6-7. Distilling off the solvent yields the crude artesunate which on silica gel column purification gives 96 % of pure artesunate. The process is complex and time consuming as it involves chromatographic purification step.
Thus, there is a need for an improved process for the conversion of artemisinin to its ester derivative, that is time efficient, simple and involves the use of lower ratio of reactants as compared to the methods available in the prior art.
SUMMARY OF THE INVENTION
The present invention relates to a process for synthesis of ester derivatives of artemisinin comprising reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound; esterifying in presence of succinic anhydride and imidazole or its derivative as a catalyst, in an aprotic solvent and isolating the ester derivative of artemisinin.
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.
DESCRIPTION OF THE INVENTION
The present disclosure provides a process for preparing ester derivative of artemisinin that comprises:
(a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound in a solvent mixture consisting of an aprotic solvent and a C 3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes;
(b) esterifying the dihydroartemisinin in presence of succinic anhydride and imidazole or its derivative as a catalyst in an aprotic solvent at a temperature in the range of 20°C to 35°C for 10 to 210 minutes to get a crude product;
(c) isolating the ester derivative of artemisinin by crystallization from crude product.
An embodiment of the present disclosure provides a process for preparing ester derivative of artemisinin wherein the ratio of artemisinin to sodium borohydride is in the range of 1 :0.1 to 1 :0.5 w/w.
Another embodiment of the present disclosure provides a process wherein the dihydroxy compound is a C 2 -C 3 diol selected from a group consisting of ethanediol, 1 ,2- propanediol and their mixtures.
Another embodiment of the present disclosure provides a process wherein the dihydroxy compound is 1 ,2-propanediol.
Yet another embodiment of the present disclosure provides a process wherein ratio of artemisinin to dihydroxy compound is in the range of 1 :0.2 to 1 : 1 w/w.
One embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the aprotic solvent used for the reduction is selected from a group consisting of chloroform, dichloromethane, toluene, ethyl acetate and hexane. Further embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the aprotic solvent used for the reduction is hexane.
Another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the C 3 alcohol is either isopropanol or n-propanol.
Still another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the C 3 alcohol is isopropanol.
An embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein reduction is carried out at a temperature range of 15 to 25°C in 5 to 30 minutes.
Another embodiment of the present invention provides a process wherein the dihydroxy compound insitu modifies the reducing agent in presence of hexane and isopropanol to produce dihydroartemisinin which is further esterified to give ester derivative of dihydroartemisinin.
Yet another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the imidazole derivative is N-(Ci-C 3 ) alkylimidazole. Yet another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the imidazole derivative is selected from a group consisting of 4-methyl imidazole and 5-methyl imidazole.
Yet another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the imidazole derivative is N-methylimidazole. Further embodiment of the present invention is a process wherein the ratio of artemisinin to imidazole or its derivative (catalyst) is in the range of 1 : 0.1 to 1 : 0.5 w/w.
Still another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the aprotic solvent used for esterification is selected from a group consisting of chloroform, tetrahydrofuran, dichloromethane, acetonitrile, and 1,4-dioxane.
Another embodiment of the present invention is a process for preparing ester derivative of artemisinin wherein the aprotic solvent used for esterification is dichloromethane .
Further embodiment of the present invention is a process preparing ester derivative of artemisinin wherein the esterification is carried out at a temperature range of 25 to 35°C in 15 to 40 minutes.
An embodiment of the present invention provides a process for preparation of ester derivative of artemisinin wherein after esterification, the pH of the reaction mixture is adjusted to 5-6 and the organic layer is washed with water, dried and concentrated to obtain the ester derivative of artemisinin as oily mass that is further crystallized with mixture of water and methanol or ethanol or acetone to obtain artesunate in high yield.
One embodiment of the present invention is a process preparing ester derivative of artemisinin wherein crystallization of ester derivative is carried out with a mixture of water and methanol or ethanol or acetone. Another embodiment of the present invention is a process preparing ester derivative of artemisinin wherein the yield of the artesunate obtained from artemisinin is in the range of 100-110 % w/w.
The present disclosure further provides a process for preparing ester derivative, of artemisinin that comprises: (a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of hexane and isopropanol at a temperature ranging from 15 to 20°C in 20 to 25 minutes;
(b) esterifying the dihydroartemisinin in presence of succinic anhydride and imidazole in dichloromethane at a temperature in the range of 25°C to 35°C for 25 to 210 minutes to get a crude product;
(c) isolating the ester derivative of artemisinin by crystallization from crude product.
The applicant used the process of US Patent No. 6677463 for the conversion of artemisinin to artesunate using the dihydroxy compound of the present invention, as
described in Reference examples A and B. The applicants observed that when 1, 2- propanediol was used as the dihydroxy compound, dihydroartemisinin was produced in traces and had a lot of impurities and no ester derivative was formed.
Further, the applicant found that the imidazole catalyst of the present invention speeds up the rate of esterification reaction as compared to the triethylamine used in the prior art process of US Patent No. 6677463. Three separate reactions were carried out by using the same molar equivalent ratio of artemisinin to catalyst (imidazole or triethylamine) as described in reference examples C, D & E. It was observed that when the esterificaton step was performed with imidazole as catalyst, the time taken for the completion of the reaction was 40 minutes and the yield of artesunate was 100% (Reference example C). When triethylamine was used as catalyst in the same molar equivalence ratio (Reference example D) the yield of artesunate was 70% in 40 min of the reaction. The yield of artesunate increased to 80% when the reaction using triethylamine was prolonged to 120 min (Reference example E). These experimental results shows that imidazole acts as a more efficient catalyst in a different way than the aliphatic amine catalyst as disclosed in the prior art.
Example 1 discloses the process for obtaining artesunate. The process involves reducing artemisinin to dihydroartemisinin in presence of 1, 2-propanediol and sodium borohydride in a solvent mixture of hexane and isopropanol to give dihydroartemisinin in a yield of 92%. The ratio of artemisinin to 1 , 2-propanediol is 1 :0.66 w/w and the ratio of artemisinin to sodium borohydride is 1 :0.33 w/w. The high yield is attributed to the combination of 1 , 2-propanediol and sodium borohydride in a solvent mixture of hexane and isopropanol that could not be derived from prior art. The dihydroartemisinin is esterified using succinic anhydride and imidazole to give the artesunate in a yield of 100% in 40 min. The ratio of artemisinin to succinic anhydride is 1 :0.52 w/w and that of artemisinin to imidazole is 1 :0.2 w/w. Further, high yield of artesunate obtained in less time was due to imidazole catalyst that accelerates the rate of reaction. Moreover, the process of the present disclosure does not employ purification over silica gel as is in the
prior art, but the pure compound is obtained by simple crystallization using suitable solvent.
Example 2 describes the process for obtaining artesunate. The process involves reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole to give the artesunate in a yield of
100% in 25 min. The ratio of artemisinin to succinic anhydride is 1 :0.52 w/w and that of artemisinin to imidazole is 1 :0.3 w/w.
Example 3 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin in presence of 1, 2-propanediol and sodium borohydride in a solvent mixture of hexane and isopropanol to give dihydroartemisinin in a yield of 88% in 40 min. The ratio of artemisinin to 1, 2-propanediol is 1 :0.8 w/w and the ratio of artemisinin to sodium borohydride is 1 :0.4 w/w. The dihydroartemisinin is esterified using succinic anhydride and imidazole to give the artesunate in a yield of 86%. The ratio of artemisinin to succinic anhydride is 1 :0.52 w/w and that of artemisinin to imidazole is 1 :0.2 w/w.
Example 4 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole to give the artesunate in a yield of 90% in 210 min. The ratio of artemisinin to succinic anhydride is 1 :0.52 w/w and that of artemisinin to imidazole is 1 :0.1 w/w.
Example 5 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole in dichloromethane to give the artesunate in a yield of 92% in 60 min. The ratio of artemisinin to succinic anhydride is 1:0.44 w/w and the ratio of artemisinin to imidazole is 1 :0.2 w/w.
Example 6 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole in acetonitrile to give the artesunate in a yield of
92% in 180 min. The ratio of artemisinin to succinic anhydride is 1:0.52 w/w and that of artemisinin to imidazole is 1 :0.2 w/w.
Example 7 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole in 1 ,4-dioxane to give the artesunate in a yield of
62% in 180 min. The ratio of artemisinin to succinic anhydride is 1 :0.44 w/w and that of artemisinin to imidazole is 1 :0.2 w/w.
Example 8 describes the process for obtaining artesunate involving reducing artemisinin to dihydroartemisinin as in example 1. The dihydroartemisinin is esterified using succinic anhydride and imidazole in chloroform to give the artesunate in a yield of
82% in 40 min. The ratio of artemisinin to succinic anhydride is 1 :0.52 w/w and that of artemisinin to imidazole is 1 :0.2 w/w.
The present disclosure provides a simple, time saving and efficient process for preparing ester derivative of artemisinin. The invention is illustrated in detail by the following examples and should not be construed as limitation.
EXAMPLES Example 1 Artemisinin (1.0 g) and 1, 2-propanediol (0.66 g) was added to a mixture of isopropanol (3.5 ml) and hexane (10 ml) and the suspension was stirred for 2 minutes at 2O 0 C followed by the addition of Sodium borohydride (0.33 gm). After 2 minutes of stirring, dihydroartemisinin started precipitating and the reaction mixture was further stirred for about 8 minutes at 2O 0 C. Water (10 ml) was added to the reaction mixture and stirred for 10 minutes at 10 0 C. Solid was filtered, washed with hexane (2 * 20 ml) and dried to yield 0.92 g (92% w/w) dihydroartemisinin.
Dihydroartemisinin (0.92 g) was stirred in dichloromethane (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.52 g) and imidazole (0.2 g) were added to this solution and stirred for 40 minutes. The pH of reaction mixture was adjusted to 5-6
and organic layer was washed with water, dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 x 2ml) and dried to yield 1.0 g of artesunate. The overall yield of artesunate was 100 % w/w.
Example 2
Reduction of artemisinin to dihydroartemisinin was carried out as described in Example 1. Dihydroartemisinin (0.92 g) was stirred in dichloromethane (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.52 g) and imidazole (0.3 g) were added to this solution and stirred for 25 minutes. The pH of reaction mixture was adjusted to 5-6 and organic layer was washed with water, dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 χ 2 ml) and dried to yield 1.0 g of artesunate. The overall yield of artesunate was 100 % w/w.
Example 3
Artemisinin (1.0 g) and 1, 2-propanediol (0.8 g) was added to a mixture of isopropanol (3.5 ml) and hexane (10 ml) and the suspension was stirred for 2 minutes at 2O 0 C followed by the addition of Sodium borohydride (0.4 g). After 2 minutes of stirring, dihydroartemisinin started precipitating and the reaction mixture was further stirred for about 8 minutes at 20 0 C. Water (7.5 ml) was added to the reaction mixture and stirred for 10 minutes at 10 0 C. Solid was filtered, washed with hexane (2 ^ 2 ml) and dried to yield 0.88 g (88% w/w) dihydroartemisinin.
Dihydroartemisinin (0.88 g) was stirred in dichloromethane (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.52 g) and imidazole (0.2 g) were added to this solution and stirred for 40 minutes. The pH of reaction mixture was adjusted to 5-6
and organic layer was washed with water, dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 x 2ml) and dried to yield 0.86 g of artesunate. The overall yield of artesunate was 86 % w/w.
Example 4
Reduction of artemisinin to dihydroartemisinin was carried out as described in Example 1. Dihydroartemisinin (0.92 g) was stirred in dichloromethane (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.52 g) and imidazole (0.1 g) were added to this solution and stirred for 210 minutes. The pH of reaction mixture was adjusted to 5-6 and organic layer was washed with water, dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 x 2 ml) and dried to yield 0.9 g of artesunate. The overall yield of artesunate was 90 % w/w.
Example 5
Reduction of artemisinin to dihydroartemisinin was carried out as described in Example 1. Dihydroartemisinin (0.92 g) was stirred in dichloromethane (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.44 g) and imidazole (0.2 g) were added to this solution and stirred for 60 minutes. The pH of reaction mixture was adjusted to 5-6 and organic layer was washed with water, dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 x 2 ml) and dried to yield 0.92 g of artesunate. The overall yield of artesunate was 92 % w/w.
Example 6
Reduction of artemisinin to dihydroartemisinin was carried out as described in
Example 1. Dihydroartemisinin (0.92 g) was stirred in acetonitrile (10 ml) for 2 minutes at room temperature. Succinic anhydride (0.52 g) and imidazole (0.2gm) were added to this solution and stirred for 180 minutes. The pH of reaction mixture was adjusted to 5-6 and it was extracted with dichloromethane (10 ml). The organic layer was washed with water (20 ml), dried and concentrated to oily mass. The oily mass was dissolved in methanol (1.5 ml) and stirred for 2 min to obtain a clear solution. Water (ImI) was added dropwise to this solution to start the precipitation of artesunate and the suspension was stirred for 5 minutes. The solid was filtered, washed with cold water (2 x 2 ml) and dried to yield 0.92 g of artesunate. The overall yield of artesunate was 92 % w/w.
Example 7 The experiment was carried out as described in example 6, with the difference that acetonitrile was replaced by 1,4-dioxane as solvent for esterification, . The yield of ester derivative obtained was 0.62 g (overall yield is 62% w/w).
Example 8
The experiment was carried out as described in example 1, with the difference that dichloromethane was replaced by chloroform as solvent for esterification. The yield of ester derivative obtained is 0.82 g (overall yield is 82.0% w/w).
REFERENCE EXAMPLES Example A
Artemisinin (0.5 g) and 1 ,2-propanediol (2.0 g) were stirred in 1,4-dioxan (10 ml) at room temperature for 5 minutes. Sodium borohydride (2.5 g) was added slowly for 10 minutes and the reaction mixture was stirred for about 2 hours at room temperature (20- 30°C). A semisolid thick mass was formed. TLC showed the presence of polar impurity. Succinic anhydride (0.25 g) and triethylamine (1.0 ml) were added at room temperature and the reaction mixture was stirred further for 2 hours at room temperature. The
completion of the reaction was checked by TLC. It was observed that no ester product formation took place. Example B
Artemisinin (0.5 g) and 1 ,2-propanediol (2.0 g) were stirred in 1,4-dioxan (10 ml) at room temperature for 5 minutes. Sodium borohydride (0.25 g) was added slowly for 10 minutes and the reaction mixture was stirred for about 2 hours at room temperature (20- 30°C). A semisolid thick mass was formed. TLC showed polar impurity formation with traces of dihydroartemisinin. Succinic anhydride (0.25 g) and triethylamine (1.0 ml) were added at room temperature and the reaction mixture was stirred further for 2 hours at room temperature. The completion of the reaction was checked by TLC and it was observed that no ester product formation took place. Example C
Artemisinin (0.5g) and 1, 2-propanediol (0.33 g) was added to a mixture of isopropanol (1.75 ml) and hexane (5 ml) and the suspension was stirred for 2 minutes at 2O 0 C followed by the addition of Sodium borohydride (0.165 g). After 2 minutes of stirring, dihydroartemisinin started precipitating and the reaction mixture was further stirred for about 8 minutes at 20 0 C. Water (5 ml) was added to the reaction mixture and stirred for 10 minutes at 1O 0 C. Solid was filtered, washed with hexane (2 x 10 ml) and dried to yield 0.46 g (92% w/w) dihydroartemisinin. Dihydroartemisinin (0.46 g) was stirred in dichloromethane (5 ml) for 2 minutes at room temperature. Succinic anhydride (0.25 g) and imidazole (0.1 gm) were added to this solution and stirred for 40 minutes. The pH of reaction mixture was adjusted to 5-6 and organic layer was washed with water. Organic layer was dried and concentrated to thick mass. Thick mass was dissolved in methanol (0.75ml) and stirred for 2 min to obtain a clear solution. To this solution water (0.5ml) was added dropwise. Artesunate starts to precipitate, suspension is stirred for next 5 minutes and solid is filtered, washed with cold water (2 xlml) and dried to yield 0.5g of artesunate. The overall yield of artesunate is 100 % w/w.
Example D
Artemisinin (0.5g) and 1, 2-propanediol (0.33 g) was added to a mixture of isopropanol (1.75 ml) and hexane (5 ml) and the suspension was stirred for 2 minutes at 2O 0 C followed by the addition of Sodium borohydride (0.165 g). After 2 minutes of stirring, dihydroartemisinin started precipitating and the reaction mixture was further stirred for about 8 minutes at 20 0 C. Water (5 ml) was added to the reaction mixture and stirred for 10 minutes at 10 0 C. Solid was filtered, washed with hexane (2 x 10 ml) and dried to yield 0.46 g (92% w/w) dihydroartemisinin.
Dihydroartemisinin (0.46 g) was stirred in dichloromethane (5 ml) for 2 minutes at room temperature. Succinic anhydride (0.25 g) and triethylamine (0.2 ml) were added to this solution and stirred for 40 minutes. The pH of reaction mixture was adjusted to 5-6 and organic layer was washed with water. Organic layer was dried and concentrated to thick mass. Thick mass was dissolved in methanol (0.75ml) and stirred for 2 min to obtain a clear solution. To this solution water (0.5ml) was added dropwise. Artesunate starts to precipitate, suspension is stirred for next 5 minutes and solid is filtered, washed with cold water (2 xlml) and dried to yield 0.35 g of artesunate. The overall yield of artesunate is 70 % w/w.
Example E
Artemisinin (0.5g) and 1, 2-propanediol (0.33 g) was added to a mixture of isopropanol (1.75 ml) and hexane (5 ml) and the suspension was stirred for 2 minutes at
2O 0 C followed by the addition of Sodium borohydride (0.165 g). After 2 minutes of stirring, dihydroartemisinin started precipitating and the reaction mixture was further stirred for about 8 minutes at 2O 0 C. Water (5 ml) was added to the reaction mixture and stirred for 10 minutes at 10 0 C. Solid was filtered, washed with hexane (2 x 10 ml) and dried to yield 0.46 g (92% w/w) dihydroartemisinin.
Dihydroartemisinin (0.46 g) was stirred in dichloromethane (5 ml) for 2 minutes at room temperature. Succinic anhydride (0.25 g) and triethylamine (0.2 ml) were added to this solution and stirred for 120 minutes. The pH of reaction mixture was adjusted to 5-
6 and organic layer was washed with water. Organic layer was dried and concentrated to thick mass. Thick mass was dissolved in methanol (0.75ml) and stirred for 2 min to
obtain a clear solution. To this solution water (0.5ml) was added dropwise. Artesunate starts to precipitate, suspension is stirred for next 5 minutes and solid is filtered, washed with cold water (2 x lml) and dried to yield 0.40 g of artesunate. The overall yield of artesunate is 80 % w/w.
Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein.