WO2008087666A1 - Preparative process for ether derivative of artemisinin - Google Patents
Preparative process for ether derivative of artemisinin Download PDFInfo
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- WO2008087666A1 WO2008087666A1 PCT/IN2008/000039 IN2008000039W WO2008087666A1 WO 2008087666 A1 WO2008087666 A1 WO 2008087666A1 IN 2008000039 W IN2008000039 W IN 2008000039W WO 2008087666 A1 WO2008087666 A1 WO 2008087666A1
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- artemisinin
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- dihydroartemisinin
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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- the present disclosure relates to a process for preparation of ether derivatives of artemisinin involving reduction of artemisinin to dihydroartemisinin followed by its etherification.
- 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.
- Arteether an 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.
- CIMAP Central Institute of Medicinal and Aromatic Plants
- Brossi et al. (J. Med. Chem., 1988, 31, 646-649) disclosed a two step process for the preparation of arteether describing, reduction of artemisinin to dihydroartemisinin with 79% yield using excess of sodium borohydride in methanol at 0 to -5 0 C in 3 hours.
- the dihydroartemisinin was converted to arteether in benzene and ethanol mixture using BF 3 etherate at 70 0 C in 1 hour.
- Column chromatographic purification of crude arteether isolated from the reaction mixture yielded alpha and beta arteether in qualitative yield. Lin et al. (J. Med.
- Chem., 1995, 38, 764-770 reported a method of using BF 3 etherate for conversion of dihydroartemisinin to arteether in anhydrous ether at room temperature for 24 hours followed by silica gel chromatography to yield 40-90% pure arteether.
- U.S. Patent No. 6,346,631 discloses conversion of dihydroartemisinin to arteether using trialkylorthoformate in alcohol at 4O 0 C for 10 hours in quantitative yield.
- Singh et al. (Tetrahedron Letters, 2002, 43, 7235-7237) disclosed a single pot conversion of artemisinin to its ether derivatives.
- US 6,750,356 disclosed a single pot conversion of artemisinin to arteether.
- the reduction of artemisinin to dihydroartemisinin was carried out by sodium borohydride in presence of polyhydroxy catalyst followed by conversion to arteether in presence of acid catalyst in 4 hours.
- Column chromatography of crude arteether yielded 80% pure alpha beta arteether. The process is time consuming and tedious as it involves purification step by column chromatography.
- the ratio of artemisinin to polyhydroxy catalyst (1:2-5 w/w), ⁇ atio of artemisinin to sodium borohydride (1 :0.5-0.7 w/w) and ratio of artemisinin to acid catalyst (1 :3-4 w/w) used is very high.
- the present invention relates to a process for synthesis of ether derivative of artemisinin comprising reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound; etherifying in presence of an acid catalyst and an alcohol and isolating the ether derivative of artemisinin.
- the present invention provides a process for synthesis of ether derivative of artemisinin comprising of:
- One embodiment of the present invention provides a process wherein the dihydroxy compound is a C 2 -C 3 diol that is selected from a group consisting of ethanediol, 1 ,2-propanediol and their mixtures.
- aprotic solvent is selected from a group consisting of chloroform, dichloromethane, toluene, ethyl acetate and hexane.
- One aspect of the present invention provides a process wherein the C 3 alcohol is either isopropanol or n-propanol.
- Further embodiment of the present invention provides a process wherein the ratio of artemisinin to dihydroxy compound is in the range of 1 :0.5 to 1 :0.8 w/w.
- 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 etherified to give ether derivative of dihydroartemisinin.
- An embodiment of the present invention is a process wherein artemisinin is reduced to dihydroartemisinin at a temperature in the range of 15 to 25°C in 5 to 30 minutes.
- Another embodiment of the present invention provides a process wherein the acid catalyst is selected from a group consisting of sulfuric acid, phosphoric acid, anhydrous hydrochloric acid in gaseous form and alcoholic hydrochloric acid.
- Further embodiment of the present invention provides a process wherein the acid catalyst is sulfuric acid.
- Another embodiment of the present invention provides a process wherein ratio of artemisinin to acid catalyst is in the range of 1 : 0.32 to 1 :1.1 w/w.
- An embodiment of the present invention provides a process wherein the alcohol used in etherif ⁇ cation is either methanol or ethanol.
- One embodiment of the present invention provides a process wherein dihydroartemisinin obtained after reduction is converted to ether derivative at a temperature range of 25 to 35°C in 15 to 40 minutes.
- An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin that is either alpha beta arteether or alpha beta artemether.
- An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin wherein the ether derivative obtained is alpha beta artemether when the alcohol used in etherification is methanoHvhile the obtained ether derivative is alpha beta arteether when the alcohol used in etherification is ethanol.
- An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin wherein after etherification, the obtained ether derivative of artemisinin is isolated by separating the organic layer by adding water; and subjecting the organic layer to washing, drying and concentrating to obtain the ether derivative of artemisinin.
- Another aspect of the present invention provides a process for preparing beta ether 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) suspending the dihydroartemisinin in hexane and etherifying in presence of an acid catalyst and an alcohol at a temperature in the range of 20°C to 50 0 C for 10 to 60 minutes; c) isolating alpha beta ether derivative of artemisinin; and e) treating alpha beta ether derivative of artemisinin with a hydroalcoholic solution to precipitate beta ether derivative.
- Another aspect of the present invention provides a process for preparing beta ether derivative of artemisinin wherein the hydroalcoholic solution used for precipitation of the beta derivative is methanol, ethanol or their mixture in water.
- An aspect of the present invention provides a process for preparing beta artemether that comprises of: a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of an hexane and isopropanol at a temperature ranging from 15 to 25°C in 5 to
- beta arteether Another aspect of the present invention provides a process for preparing beta arteether that comprises of: a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of an hexane and isopropanol at a temperature ranging from 15 to 25°C in 5 to 30 minutes;
- An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin with a yield in the range of 85-90% w/w. Further embodiment of the present invention provides a process for conversion of artemisinin to its ether derivative that is time efficient, simple and involves the use of lower ratio of reactants.
- Example 1 discloses the process for obtaining alpha beta arteether.
- 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 etherified using sulfuric acid and ethanol to give the alpha beta arteether in a yield of 92%.
- the ratio of artemisinin to acid catalyst is 1 :0.74 w/w.
- high yield of alpha beta arteether obtained due to sulfuric acid catalyst and ethanol is not shown in prior art.
- Example 2 further describes the isolation of beta arteether from the alpha beta arteether obtained by using the same ratio of reactants as that in example 1 using methanol in water. Beta arteether is obtained in a yield of about 55%.
- Example 3 describes the process for obtaining alpha beta artemether.
- 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 etherified using sulfuric acid and methanol to give the alpha beta artemether in a yield of 92%.
- the ratio of artemisinin to acid catalyst is 1 :0.74 w/w.
- high yield of alpha beta artemether obtained due to sulfuric acid catalyst and methanol is not shown in prior art.
- Example 4 describes the isolation of beta artemether from the alpha beta artemether obtained by using the same ratio of reactants as in example 3 using methanol in water. Beta artemether is obtained in a yield of about 57%.
- Example 5 discloses the process for obtaining alpha beta arteether.
- 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 an yield of 80%.
- ratio of artemisinin to sodium borohydride was decreased to 1:0.26 w/w from 1 :0.33 w/w used in examples 1-4 and the ratio of artemisinin to 1, 2-propanediol was decreased to 1:0.53 w/w from 1:0.66 w/w used in examples 1-4; there was a decrease in the yield of dihydroartemisinin.
- the ratio of artemisinin to sulphuric acid was decreased to 1 :0.58 w/w from 1 :0.74 w/w used in examples 1-4 and 80% yield of alpha beta arteether was obtained.
- Example 6 in the reduction step of reducing artemisinin to dihydroartemisinin in presence of 1 ,2-propanediol and sodium borohydride in a solvent mixture of hexane and isopropanol, the ratio of artemisinin to reducing agent sodium borohydride was increased to 1:0.4 w/w from 1:0.33 w/w used in examples 1-4 and the ratio of artemisinin to 1, 2-propanediol was increased to 1:0.8 w/w from 1:0.66 w/w used in examples 1-4 ; a yield of 88% was obtained that was more than that obtained in example 5 but less than that obtained in examples 1-4.
- the optimum ratio of artemisinin to 1, 2-propanediol and artemisinin to sodium borohydride is as used in examples 1-4 and example 7 that gives a yield of 92% dihydroartemisinin.
- the ratio of artemisinin to sulphuric acid was 1 :0.64 w/w and a yield of about 83% alpha beta arteether was obtained.
- Example 7 describes the preparation of alpha beta arteether where the reduction step is as described in examples 1-4 but in the etherification step the ratio of artemisinin to sulphuric acid is reduced to 1:0.32 w/w. It was found that on reducing the ratio of artemisinin to acid catalyst the yield of alpha beta arteether got reduced to 78%.
- Example 8 describes the preparation of alpha beta arteether where the reduction step is as in examples 1-4 and 7 but the ratio of artemisinin to sulphuric acid is increased to 1:1.1 w/w in the etherification step. It was found that on increasing the ratio of artemisinin to acid catalyst the yield of alpha beta arteether got reduced to 70%. Thus the optimum ratio of artemisinin to sodium borohydride; artemisinin to 1 ,2-propanediol and artemisinin to acid catalyst is as used in examples 1-4.
- An embodiment of the present invention is a process that utilizes artemisinin to dihydroxy catalyst in the ratio 1 :0.5-0.8 w/w, artemisinin to sodium borohydride in the ratio 1 :0.2 - 0.4 w/w and artemisinin to acid catalyst in the ratio 1 :0.32-1.1 w/w to obtain
- One more embodiment of the present invention is a process for preparing dihydroartemisinin from artemisinin, said process comprising reacting artemisinin 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.
- the present invention discloses an improved process for the preparation of ether derivative of artemisinin that overcome the shortcomings of the prior art.
- Dihydroartemisinin (9.2 g) was stirred in hexane (100 ml) for 2 minutes at room temperature and a solution of sulphuric acid (4 ml) in ethanol (20 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (75 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 75 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 9.2 g of alpha beta arteether in semisolid form. The overall yield was about 92 % w/w. In this process, a high yield of dihydroartemisinin was obtained which resulted in higher yield of alpha beta arteether.
- Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.4 ml) in ethanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that was dissolved in methanol (2 ml) and stirred for 2 minutes to obtain a clear solution.
- Beta arteether 0.552 g. The overall yield of beta arteether was about 55 % w/w.
- Dihydroartemisinin (9.2 g) was stirred in hexane (100 ml) for 2 minutes at room temperature and a solution of sulphuric acid (4 ml) in methanol (20 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (75 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 75 ml) and dried over sodium sulphate.
- the dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 9.2 g of alpha beta artemether in semisolid form.
- the overall yield was about 92 % w/w. In this process, a high yield of dihydroartemisinin was obtained which resulted in higher yield of alpha beta artemether.
- Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.4 ml) in methanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate.
- the dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that was dissolved in methanol (2 ml) and stirred for 2 minutes to obtain a clear solution.
- Water (1 ml) was added dropwise resulting in the precipitation of Beta artemether and the suspension was stirred for 5 minutes at 1O 0 C.
- the precipitate was filtered, washed with cold water (2 x 2ml) and dried to yield beta artemether (0.57 g).
- the overall yield of beta artemether was about 57% w/w.
- Dihydroartemisinin (0.8 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.32 ml) in ethanol (2 ml) was added. After
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Abstract
The present invention relates to a process for synthesis of ether derivative of artemisinin by reducing artemisinin to dihydroartemisinin using a mixture of sodium borohydride and a dihydroxy compound, followed by etherification in presence of an acid catalyst and an alcohol.
Description
PREPARATIVE PROCESS FOR ETHER DERIVATIVES OF ARTEMISININ
FIELD OF INVENTION
The present disclosure relates to a process for preparation of ether derivatives of artemisinin involving reduction of artemisinin to dihydroartemisinin followed by its etherification.
BACKGROUND OF THE INVENTION
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.
Arteether, an 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.
Brossi et al. (J. Med. Chem., 1988, 31, 646-649) disclosed a two step process for the preparation of arteether describing, reduction of artemisinin to dihydroartemisinin with 79% yield using excess of sodium borohydride in methanol at 0 to -50C in 3 hours. In the second step, the dihydroartemisinin was converted to arteether in benzene and ethanol mixture using BF3 etherate at 700C in 1 hour. Column chromatographic purification of crude arteether isolated from the reaction mixture yielded alpha and beta arteether in qualitative yield.
Lin et al. (J. Med. Chem., 1995, 38, 764-770) reported a method of using BF3 etherate for conversion of dihydroartemisinin to arteether in anhydrous ether at room temperature for 24 hours followed by silica gel chromatography to yield 40-90% pure arteether.
Bhakuni et al. (Indian J. Chemistry, 1995, 34B, 529-530) described the preparation of arteether, artemether and other ether derivatives from dihydroartemisinin using chlorotrimethylsilane as catalyst and appropriate alcohol in benzene in 2-4 hours at room temperature.
U.S. Patent No. 6,346,631 discloses conversion of dihydroartemisinin to arteether using trialkylorthoformate in alcohol at 4O0C for 10 hours in quantitative yield.
Singh et al. (Tetrahedron Letters, 2002, 43, 7235-7237) disclosed a single pot conversion of artemisinin to its ether derivatives. The process described reduction of artemisinin with sodium borohydride/Amberlyst-15 combination and its in situ conversion to the desired ether derivative by addition of appropriate alcohol at room temperature for 72 hours. Column chromatography of crude product yielded 55% pure arteether.
US 6,750,356 disclosed a single pot conversion of artemisinin to arteether. The reduction of artemisinin to dihydroartemisinin was carried out by sodium borohydride in presence of polyhydroxy catalyst followed by conversion to arteether in presence of acid catalyst in 4 hours. Column chromatography of crude arteether yielded 80% pure alpha beta arteether. The process is time consuming and tedious as it involves purification step by column chromatography. Also, the ratio of artemisinin to polyhydroxy catalyst (1:2-5 w/w),τatio of artemisinin to sodium borohydride (1 :0.5-0.7 w/w) and ratio of artemisinin to acid catalyst (1 :3-4 w/w) used is very high.
Thus, there is a need for an improved process for the conversion of artemisinin to its ether 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 ether derivative of artemisinin comprising reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound; etherifying in presence of an acid catalyst and an alcohol and isolating the ether 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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for synthesis of ether derivative of artemisinin 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 C3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes; (b) suspending the dihydroartemisinin in hexane and etherifying in presence of an acid catalyst and an alcohol at a temperature in the range of 20°C to 50°C for 10 to 60 minutes; and (c) isolating said ether derivative of artemisinin.
Artemisinin Dihydroartemisinin
Ether derivative
One embodiment of the present invention provides a process wherein the dihydroxy compound is a C2-C3 diol that is selected from a group consisting of ethanediol, 1 ,2-propanediol and their mixtures.
Another embodiment of the present invention provides a process wherein the aprotic solvent is selected from a group consisting of chloroform, dichloromethane, toluene, ethyl acetate and hexane.
Further embodiment of the present invention provides a process wherein the aprotic solvent is hexane.
One aspect of the present invention provides a process wherein the C3 alcohol is either isopropanol or n-propanol.
Another aspect of the present invention provides a process wherein the C3 alcohol is isopropanol. Yet another aspect of the present invention provides a process wherein the ratio of artemisinin to sodium borohydride is in the range of 1 :0.2 to 1 :0.4 w/w.
Further embodiment of the present invention provides a process wherein the ratio of artemisinin to dihydroxy compound is in the range of 1 :0.5 to 1 :0.8 w/w.
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 etherified to give ether derivative of dihydroartemisinin.
An embodiment of the present invention is a process wherein artemisinin is reduced to dihydroartemisinin at a temperature in the range of 15 to 25°C in 5 to 30 minutes.
Another embodiment of the present invention provides a process wherein the acid catalyst is selected from a group consisting of sulfuric acid, phosphoric acid, anhydrous hydrochloric acid in gaseous form and alcoholic hydrochloric acid.
Further embodiment of the present invention provides a process wherein the acid catalyst is sulfuric acid.
Another embodiment of the present invention provides a process wherein ratio of artemisinin to acid catalyst is in the range of 1 : 0.32 to 1 :1.1 w/w.
An embodiment of the present invention provides a process wherein the alcohol used in etherifϊcation is either methanol or ethanol. One embodiment of the present invention provides a process wherein dihydroartemisinin obtained after reduction is converted to ether derivative at a temperature range of 25 to 35°C in 15 to 40 minutes.
An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin that is either alpha beta arteether or alpha beta artemether. An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin wherein the ether derivative obtained is alpha beta artemether when the alcohol used in etherification is methanoHvhile the obtained ether derivative is alpha beta arteether when the alcohol used in etherification is ethanol.
An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin wherein after etherification, the obtained ether derivative of artemisinin is isolated by separating the organic layer by adding water; and subjecting the organic layer to washing, drying and concentrating to obtain the ether derivative of artemisinin.
One more embodiment of the present invention provides a process for synthesis of alpha beta artemether comprising of:
(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 25°C in 5 to 30 minutes;
(b) suspending the dihydroartemisinin in hexane and etherifying in presence of sulfuric acid and methanol at a temperature in the range of 25°C to 35°C for 15 to 40 minutes; and
(c) isolating alpha beta artemether. Another embodiment of the present invention provides a process for synthesis of alpha beta arteether comprising of:
(a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of an hexane and isopropanol at a temperature ranging from 15 to 25°C in 5 to 30 minutes;
(b) suspending the dihydroartemisinin in hexane and etherifying in presence of sulfuric acid and ethanol at a temperature in the range of 25°C to 35°C for 15 to 40 minutes; and
(c) isolating alpha beta arteether. Another aspect of the present invention provides a process for preparing beta ether 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 C3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes; b) suspending the dihydroartemisinin in hexane and etherifying in presence of an acid catalyst and an alcohol at a temperature in the range of 20°C to 500C for 10 to 60 minutes; c) isolating alpha beta ether derivative of artemisinin; and e) treating alpha beta ether derivative of artemisinin with a hydroalcoholic solution to precipitate beta ether derivative.
Another aspect of the present invention provides a process for preparing beta ether derivative of artemisinin wherein the hydroalcoholic solution used for precipitation of the beta derivative is methanol, ethanol or their mixture in water.
An aspect of the present invention provides a process for preparing beta artemether that comprises of: a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of an hexane and isopropanol at a temperature ranging from 15 to 25°C in 5 to
30 minutes;
(b) suspending the dihydroartemisinin in hexane and etherifying in presence of sulfuric acid and methanol at a temperature in the range of 25°C to 35°C for 15 to 40 minutes to obtain alpha beta artemether; (c) isolating alpha beta artemether; and
(d) treating with a hydroalcoholic solution to precipitate beta artemether. Another aspect of the present invention provides a process for preparing beta arteether that comprises of: a) reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and 1 ,2-propanediol in a solvent mixture consisting of an hexane and isopropanol at a temperature ranging from 15 to 25°C in 5 to 30 minutes;
(b) suspending the dihydroartemisinin in hexane and etherifying in presence of sulfuric acid and ethanol at a temperature in the range of 25°C to 35°C for 15 to 40 minutes to obtain alpha beta arteether;
(c) isolating alpha beta arteether; and
(d) treating with a hydroalcoholic solution to precipitate beta arteether.
An embodiment of the present invention provides a process for synthesis of ether derivative of artemisinin with a yield in the range of 85-90% w/w. Further embodiment of the present invention provides a process for conversion of artemisinin to its ether derivative that is time efficient, simple and involves the use of lower ratio of reactants.
The applicant attempted to use the experimental conditions of the process of US Patent No. 6,750,356 in the preparation of alpha beta arteether, as herein described in Reference example A and obtained a yield of 40% w/w.
Further, the applicant used the same above prior art process for the conversion of artemisinin to arteether using the dihydroxy compound of the present invention, as described in Reference example B and C. The applicants observed that the dihydroartemisinin produced in the reduction step had impurities and the yield of alpha beta arteether was 60% when 1 , 2-propanediol was used as the dihydroxy compound, as can be seen from Reference example B. Similar observation was made with Reference example C where the yield was about 52%.
The applicant also tried to obtain alpha beta arteether by prior art method by using the dihydroxy compound (1, 2-propanediol) and acid catalyst (sulphuric acid) as described in Reference example D. In this method dihydroartemisinin could not be converted to its ether derivative. It is clear from Reference example D that using dihydroxy compound (1, 2-propanediol) and acid catalyst of the present invention in the prior art process does not produce the ether derivative of artemisinin.
Example 1 discloses the process for obtaining alpha beta arteether. 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 etherified using sulfuric acid and ethanol to give the alpha beta arteether in a yield of 92%. The ratio of artemisinin to acid catalyst is 1 :0.74 w/w. Further, high yield of alpha beta arteether obtained due to sulfuric acid catalyst and ethanol is not shown in prior art. Example 2 further describes the isolation of beta arteether from the alpha beta arteether obtained by using the same ratio of reactants as that in example 1 using methanol in water. Beta arteether is obtained in a yield of about 55%.
Example 3 describes the process for obtaining alpha beta artemether. 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 etherified using sulfuric acid and methanol to give the alpha beta artemether in a yield of 92%. The ratio of artemisinin to acid catalyst is 1 :0.74 w/w. Further, high yield of alpha beta artemether obtained due to sulfuric acid catalyst and methanol is not shown in prior art. Example 4 describes the isolation of beta artemether from the alpha beta artemether obtained by using the same ratio of reactants as in example 3 using methanol in water. Beta artemether is obtained in a yield of about 57%.
Example 5 discloses the process for obtaining alpha beta arteether. 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 an yield of 80%. It was seen that as the ratio of artemisinin to sodium borohydride was decreased to 1:0.26 w/w from 1 :0.33 w/w used in examples 1-4 and the ratio of artemisinin to 1, 2-propanediol was decreased to 1:0.53 w/w from 1:0.66 w/w used in examples 1-4; there was a decrease in the yield of dihydroartemisinin. Further, in etherification the ratio of artemisinin to sulphuric acid was decreased to 1 :0.58 w/w from 1 :0.74 w/w used in examples 1-4 and 80% yield of alpha beta arteether was obtained.
In Example 6 in the reduction step of reducing artemisinin to dihydroartemisinin in presence of 1 ,2-propanediol and sodium borohydride in a solvent mixture of hexane and isopropanol, the ratio of artemisinin to reducing agent sodium borohydride was increased to 1:0.4 w/w from 1:0.33 w/w used in examples 1-4 and the ratio of artemisinin to 1, 2-propanediol was increased to 1:0.8 w/w from 1:0.66 w/w used in examples 1-4 ; a yield of 88% was obtained that was more than that obtained in example 5 but less than that obtained in examples 1-4. Thus, the optimum ratio of artemisinin to 1, 2-propanediol and artemisinin to sodium borohydride is as used in examples 1-4 and example 7 that
gives a yield of 92% dihydroartemisinin. Further, in etherification the ratio of artemisinin to sulphuric acid was 1 :0.64 w/w and a yield of about 83% alpha beta arteether was obtained.
Example 7 describes the preparation of alpha beta arteether where the reduction step is as described in examples 1-4 but in the etherification step the ratio of artemisinin to sulphuric acid is reduced to 1:0.32 w/w. It was found that on reducing the ratio of artemisinin to acid catalyst the yield of alpha beta arteether got reduced to 78%.
Example 8 describes the preparation of alpha beta arteether where the reduction step is as in examples 1-4 and 7 but the ratio of artemisinin to sulphuric acid is increased to 1:1.1 w/w in the etherification step. It was found that on increasing the ratio of artemisinin to acid catalyst the yield of alpha beta arteether got reduced to 70%. Thus the optimum ratio of artemisinin to sodium borohydride; artemisinin to 1 ,2-propanediol and artemisinin to acid catalyst is as used in examples 1-4.
Thus, the best mode of the present invention is as shown in examples 1-4 that could not be derived from the prior art.
An embodiment of the present invention is a process that utilizes artemisinin to dihydroxy catalyst in the ratio 1 :0.5-0.8 w/w, artemisinin to sodium borohydride in the ratio 1 :0.2 - 0.4 w/w and artemisinin to acid catalyst in the ratio 1 :0.32-1.1 w/w to obtain
■a high yield of high purity arteether. The yield is higher as compared to the methods employed in the prior art.
One more embodiment of the present invention is a process for preparing dihydroartemisinin from artemisinin, said process comprising reacting artemisinin with a mixture of sodium borohydride and a dihydroxy compound in a solvent mixture consisting of an aprotic solvent and a C3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes.
Thus, the present invention discloses an improved process for the preparation of ether derivative of artemisinin that overcome the shortcomings of the prior art. 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.
EXAMPLES Example 1
Artemisinin (1.0 g) and 1, 2-propanediol (0.66 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at 2O0C followed by the addition of Sodium borohydride (0.33 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred further for about 8 minutes at 200C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 1O0C. The precipitate was filtered, washed with hexane (2 x 2 ml) and dried to yield dihydroartemisinin 92% w/w (0.92 g).
Dihydroartemisinin (9.2 g) was stirred in hexane (100 ml) for 2 minutes at room temperature and a solution of sulphuric acid (4 ml) in ethanol (20 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (75 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 75 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 9.2 g of alpha beta arteether in semisolid form. The overall yield was about 92 % w/w. In this process, a high yield of dihydroartemisinin was obtained which resulted in higher yield of alpha beta arteether.
Example 2
Artemisinin (1.0 g) and 1, 2-propanediol (0.66 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at
200C followed by the addition of Sodium borohydride (0.33 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred further for about 8 minutes at 2O0C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 100C. The precipitate was filtered, washed with hexane (2 x 2 ml) and dried to yield dihydroartemisinin 92% w/w (0.92 g).
Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.4 ml) in ethanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that was dissolved in methanol (2 ml) and stirred for 2 minutes to obtain a clear solution. Water (1 ml) was added dropwise resulting in the precipitation of Beta arteether and the suspension was stirred for 5 minutes at 1O0C. The precipitate was filtered, washed with cold water (2 x 2ml) and dried to yield beta arteether (0.552 g). The overall yield of beta arteether was about 55 % w/w.
Example 3
The reaction was carried out as described in example 1, with the modifications. The modification is that a suspension of sulphuric acid in methanol was used in place of solution of sulphuric acid in ethanol and 9.2 g of alpha beta artemether was obtained with an overall yield of 92 % w/w. The details are given below.
Artemisinin (1.0 g) and 1, 2-propanediol (0.66 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at 2O0C followed by the addition of Sodium borohydride (0.33 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred further for about 8 minutes at 200C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 1O0C. The precipitate was filtered, washed with hexane (2 χ 2 ml) and dried to yield dihydroartemisinin 92% w/w (0.92 g). Dihydroartemisinin (9.2 g) was stirred in hexane (100 ml) for 2 minutes at room temperature and a solution of sulphuric acid (4 ml) in methanol (20 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (75 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 75 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room
temperature to get thick oil that gave 9.2 g of alpha beta artemether in semisolid form. The overall yield was about 92 % w/w. In this process, a high yield of dihydroartemisinin was obtained which resulted in higher yield of alpha beta artemether.
Example 4
Artemisinin (1.0 g) and 1, 2-propanediol (0.66 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at 2O0C followed by the addition of Sodium borohydride (0.33 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred further for about 8 minutes at 200C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 100C. The precipitate was filtered, washed with hexane (2 x 2 ml) and dried to yield dihydroartemisinin 92% w/w (0.92 g). Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.4 ml) in methanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that was dissolved in methanol (2 ml) and stirred for 2 minutes to obtain a clear solution. Water (1 ml) was added dropwise resulting in the precipitation of Beta artemether and the suspension was stirred for 5 minutes at 1O0C. The precipitate was filtered, washed with cold water (2 x 2ml) and dried to yield beta artemether (0.57 g). The overall yield of beta artemether was about 57% w/w.
Example 5
Artemisinin (1.0 g) and 1, 2-propanediol (0.53 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at 2O0C followed by the introduction of Sodium borohydride (0.26 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred
further for about 8 minutes at 2O0C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 1O0C. The precipitate was filtered, washed with hexane (2 x 2 ml) and dried to yield dihydroartemisinin 80% w/w (0.8 g).
Dihydroartemisinin (0.8 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.32 ml) in ethanol (2 ml) was added. After
10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 0.8 g of alpha beta arteether in semisolid form. The overall yield was about 80 % w/w.
Example 6
Artemisinin (1.0 g) and 1, 2-propanediol (0.8 g) were added to a solvent mixture of isopropanol (3.5 ml) and hexane (10 ml). The suspension was stirred for 2 minutes at
200C followed by the addition of Sodium borohydride (0.4 g). After 2 minutes of stirring, dihydroartemisinin started to precipitate out and the reaction mixture was stirred further for about 8 minutes at 2O0C. Subsequently, water (7.5 ml) was added to the reaction mixture and it was stirred for 10 minutes at 100C. The precipitate was filtered, washed with hexane (2 x 2 ml) and dried to yield dihydroartemisinin 88% w/w (0.88 g).
Dihydroartemisinin (0.88 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.35 ml) in ethanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 0.836 g of alpha beta arteether in semisolid form. The overall yield was 83.6 % w/w.
Example 7
The reduction of artemisinin to dihydroartemisinin was carried out as in example
2. Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.2 ml) in ethanol (2 ml) was added. After 25 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 x 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 0.78 g of alpha beta arteether in semisolid form with an overall yield of 78% (w/w).
Example 8
The reduction of artemisinin to dihydroartemisinin was carried out as in example 2. Dihydroartemisinin (0.92 g) was stirred in hexane (10 ml) for 2 minutes at room temperature and a solution of sulphuric acid (0.6 ml) in ethanol (2 ml) was added. After 10 minutes of stirring, a clear solution was obtained that was further stirred for about 15 minutes at room temperature and water (7.5 ml) was added with stirring for 5 minutes to separate hexane layer that was washed with water (2 * 7.5 ml) and dried over sodium sulphate. The dried hexane layer was concentrated under reduced pressure at room temperature to get thick oil that gave 0.7 g of alpha beta arteether in semisolid form with an overall yield of 70% (w/w).
REFERENCE EXAMPLES Reference Example A Artemisinin (Ig) and polyhydroxy catalyst, dextrose (5 g) were stirred in ethanol
(20ml) at room temperature for 5 minutes. Sodium borohydride (0.6 mg) was added slowly for 10 minutes and the reaction mixture was stirred for about 1 hour at room temperature (20-23°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°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 x 50 ml). 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 arteether purified over silica gel (10 g) with 0.5 to 8% ethyl acetate in hexane furnished 0.4 g of alpha beta arteether . The yield was 40% w/w and is lower than the yield obtained using the method of the present invention.
Reference Example B
Artemisinin (1 g) and dihydroxy catalyst, 1 ,2-propanediol (5 g) were stirred in ethanol (20ml) at room temperature for 5 minutes. Sodium borohydride (0.6 g) was added slowly for 10 minutes and the reaction mixture was stirred for about 1 hour at room temperature (20-250C). The reaction was monitored by TLC to check completion of the reduction step. Acid catalyst chlorotrimethysilane (3.0 ml) was added slowly at 10-230C 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 x 50 ml). 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 1.0 g. of crude arteether along with some impurities. The impure arteether purified over silica gel (10 g) with 0.5 to 8% ethyl acetate in hexane gave 60% yield of alpha beta arteether. Small portion of arteether was separated by preparative TLC into alpha and beta isomers (60% beta isomer and 40% alpha isomer). Reference Example C
The above procedure was repeated with ethanediol as dihydroxy catalyst and alpha beta arteether was obtained giving a yield of about 52 % w/w.
Reference Example D
Artemisinin (1 g) and dihydroxy catalyst, 1 ,2-propanediol (0.6 g) were stirred in ethanol (20ml) at room temperature for 5 minutes. Sodium borohydride (0.6 g) was added slowly for 10 minutes and the reaction mixture was stirred for about 1 hour at room temperature (20-25°C). Acid catalyst sulphuric acid (0.9 ml) was added slowly at 10- 23 °C and the reaction mixture was further stirred at room temperature for about 1 hour. TLC was carried out to check the completion of reaction and it was found that conversion of dihydroartemisinin to artemether was in traces and the product could not be isolated.
Claims
1. A process for preparing ether 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 C3 alcohol at a temperature ranging from 0 to 300C in 5 to 40 minutes;
(b) suspending the dihydroartemisinin in hexane and etherifying in presence of an acid catalyst and an alcohol at a temperature in the range of 200C to 500C for 10 to 60 minutes; and (c) isolating said ether derivative of artemisinin.
2. The process as claimed in claim 1, wherein ratio of artemisinin to sodium borohydride is in the range of 1 :0.2 to 1 :0.4 w/w.
3. The process as claimed in claim 1, wherein the dihydroxy compound is a C2-C3 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 :0.5 to 1 :0.8 w/w.
5. The process as claimed in claim 1, wherein the aprotic solvent is selected from a group consisting of chloroform, dichloromethane, toluene, ethyl acetate and hexane.
6. The process as claimed in claim 1, wherein the C3 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 250C in 5 to 30 minutes.
8. The process as claimed in claim 1, wherein the acid catalyst is selected from a group consisting of sulfuric acid, phosphoric acid, anhydrous hydrochloric acid in gaseous form and alcoholic hydrochloric acid.
9. The process as claimed in claim 1, wherein the acid catalyst is sulfuric acid.
10. The process as claimed in claim 1, wherein ratio of artemisinin to acid catalyst is in the range of 1 :0.32 to 1 :1.1 w/w.
11. The process as claimed in claim 1 , wherein the alcohol used in etherification is either methanol or ethanol.
12. The process as claimed in claim 1 wherein the etherification is carried out at a temperature range of 25 to 35 °C in 15 to 40 minutes.
13. The process as claimed in claim 1, wherein said ether derivative is either alpha beta arteether or alpha beta artemether.
14. The process as claimed in claim 1, wherein said ether derivative is alpha beta artemether when the alcohol used in etherification is methanol.
15. The process as claimed in claim 1, wherein said ether derivative is alpha beta arteether when the alcohol used in etherification is ethanol.
16. A process for preparing beta ether 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 C3 alcohol at a temperature ranging from 0 to 300C in 5 to 40 minutes; b) suspending the dihydroartemisinin in hexane and etherifying in presence of an acid catalyst and an alcohol at a temperature in the range of
20°C to 500C for 10 to 60 minutes; c) isolating alpha beta ether derivative of artemisinin; and e) treating alpha beta ether derivative of artemisinin with a hydroalcoholic solution to precipitate beta ether derivative.
17. The process as claimed in claim 16, wherein the hydroalcoholic solution is methanol, ethanol or mixture thereof in water.
18. The process as claimed in claim 16, wherein the beta ether derivative is beta arteether when the alcohol used in etherification is ethanol.
19. The process as claimed in claim 16, wherein the beta ether derivative is beta artemether when the alcohol used in etherification is methanol.
20. A process for preparing dihydroartemisinin from artemisinin, said process comprising reacting artemisinin with a mixture of sodium borohydride and a dihydroxy compound in a solvent mixture consisting of an aprotic solvent and a C3 alcohol at a temperature ranging from 0 to 30°C in 5 to 40 minutes.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102350293A (en) * | 2011-09-02 | 2012-02-15 | 江苏斯威森生物医药工程研究中心有限公司 | Special reaction kettle for preparing dihydroartemisinin by hydroboration reduction |
| WO2012042536A2 (en) * | 2010-09-27 | 2012-04-05 | Sequent Scientific Limited | A process for preparation of ether derivatives of dihdroartemisinin |
| CN102887907A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | New process for preparing beta-arteether by single reaction kettle method by taking artemisinin as raw material |
| CN102887908A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | Simple process for preparing artesunate by one-pot method by taking artemisinin as raw material |
| CN103145728A (en) * | 2013-04-12 | 2013-06-12 | 张梅 | Industrialized oriented synthesis method of beta-artemether |
| CN103214496A (en) * | 2013-03-15 | 2013-07-24 | 彭学东 | Simple and rapid preparation process of dihydroartemisinin |
| EP2826779A1 (en) | 2013-07-15 | 2015-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6750356B1 (en) * | 2002-12-02 | 2004-06-15 | Council Of Scientific And Industrial Research | Single pot conversion of artemisinin into arteether |
-
2008
- 2008-01-21 WO PCT/IN2008/000039 patent/WO2008087666A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6750356B1 (en) * | 2002-12-02 | 2004-06-15 | Council Of Scientific And Industrial Research | Single pot conversion of artemisinin into arteether |
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| WO2012042536A2 (en) * | 2010-09-27 | 2012-04-05 | Sequent Scientific Limited | A process for preparation of ether derivatives of dihdroartemisinin |
| WO2012042536A3 (en) * | 2010-09-27 | 2012-05-31 | Sequent Scientific Limited | A process for preparation of ether derivatives of dihdroartemisinin |
| CN102887907A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | New process for preparing beta-arteether by single reaction kettle method by taking artemisinin as raw material |
| CN102887908A (en) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | Simple process for preparing artesunate by one-pot method by taking artemisinin as raw material |
| CN102350293B (en) * | 2011-09-02 | 2013-03-20 | 江苏斯威森生物医药工程研究中心有限公司 | Special reaction kettle for preparing dihydroartemisinin by hydroboration reduction |
| CN102350293A (en) * | 2011-09-02 | 2012-02-15 | 江苏斯威森生物医药工程研究中心有限公司 | Special reaction kettle for preparing dihydroartemisinin by hydroboration reduction |
| CN103214496A (en) * | 2013-03-15 | 2013-07-24 | 彭学东 | Simple and rapid preparation process of dihydroartemisinin |
| CN103145728A (en) * | 2013-04-12 | 2013-06-12 | 张梅 | Industrialized oriented synthesis method of beta-artemether |
| EP2826779A1 (en) | 2013-07-15 | 2015-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives |
| WO2015007693A1 (en) * | 2013-07-15 | 2015-01-22 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives |
| CN105377855A (en) * | 2013-07-15 | 2016-03-02 | 马普科技促进协会 | Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives |
| US9802952B2 (en) | 2013-07-15 | 2017-10-31 | Max-Plank-Gesellschaft zur Förderung der Wissenschaften e.v. | Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives |
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