The present invention relates to simple and cost-effective processes for the preparation of ether derivatives of dihydroartemesinin. The present invention enables preparation of pure p-ether derivatives of dihydroartemesinin which are well-known antimalarial agents.
Dihydroartemesinin is derived from artemesinin, which is a sesquiterpene lactone isolated from Chinese-Vietnamese plant Artemesia annua L. Of the ether derivatives of dihydroartemesinin represented by Formula I,
(Formula Removed)
Formula I
wherein R can be alkyl, aryl or aralkyl, the p-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 malaria 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 chemotherapy.
Brossi et. al., J. Med. Chem. 31, 646-649 (1988) disclose a process for the preparation of arteether by treating a solution of dihydroartemesinin in a mixture of benzene and ethanol with BF3-etherate. Arteether is separated from the reaction mixture by column chromatography to obtain the p and a isomers in a ratio of 1:20.
EL-Feraly et. al., J. Nat. Prod. 55, 878-883 (1992) disclose a process for the preparation of arteether by treating a solution of anhydrodihydroartemesinin in absolute alcohol with p-toluenesulphonic acid. The process requires large amounts of the Lewis acid catalyst and the (3-arteether obtained as the product is contaminated with the C11-epimer and further purification needs to be carried out.
Bhakuni et. al., Ind. J. Chemistry, 34B, 529-530 (1995) disclose a process for the preparation of arteether and artemether by treating a solution of dihydroartemesinin in a mixture of the appropriate alcohol and benzene with chlorotrimethylsilane catalyst. Chlorotrimethylsilane is costly and therefore it is desirable to develop more economic processes with cheaply available reagents.
US Patent No. 6,683,193 (herein after the '193 patent) discloses a one-pot process for the preparation of artemether from artemesinin wherein artemesinin is reduced to dihydroartemesinin in methanol solvent and in the same solvent dihydroartemesinin is etherified in the presence of an acid catalyst. In situ processes lead to association of greater amounts of impurities with the desired product as compared to a process wherein the intermediate products are isolated and purified before taking them to the next step. Evidently, the a and p artemether obtained by the process of the '193 patent are separated and purified by column chromatography. The present inventors have developed simple and cost effective processes for the preparation of ether derivatives of dihydroartemesinin by employing cheaply available reagents. The present process does not require column chromatographic purification and at the same time affords preparation of pure p-isomer by simple crystallization techniques.
A first aspect of the present invention provides a process for the preparation of ether derivative of dihydroartemesinin of the Formula I,
(Formula Removed)
Formula I
wherein R represents aikyl, aryl or aralkyl, said process comprises of, a) treating dihydroarternesinin of Formula II,
(Formula Removed)
Formula II
with trialkyl borate of Formula B(OR1)3 wherein R1 represents lower alkyl group, in the presence
of an acid catalyst,
b) isolating the ether derivative of dihydroarternesinin of Formula I from the reaction mass thereof.
Dihydroarternesinin of Formula II can be prepared by reduction of artemesinin by methods known in the art or as exemplified in the present patent application. To a stirred solution of dihydroarternesinin in a suitable organic solvent is added trialkyl borate of Formula B(OR1)3 wherein R1 represents lower alkyl group, followed by an acid catalyst at about 0 to about 15°C. The reaction mixture is stirred for about 1 to about 5 hours and the reaction progress monitored by Thin Layer Chromatography. After completion of the reaction the pH of the mixture is adjusted to about 7.0 to about 8.0 with a base at about 0 to about 15°C. The resultant mixture is suitably worked up to obtain a mixture of p and a isomers of the ether derivative of dihydroarternesinin of Formula I in a ratio of about 70-80 : 30-20. From the mixture of (3 and a isomer so obtained, pure p-ether derivative of dihydroarternesinin of Formula I is obtained by recrystallization from a suitable hydrocarbon solvent.
Suitable organic solvents can be selected from the group comprising of chlorinated hydrocarbons, hydrocarbons, polar aprotic solvents or mixtures thereof. The chlorinated hydrocarbons can be
selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like Polar aprotic solvents can be selected from the group comprising of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and the like. Hydrocarbon solvents can be selected from the group comprising of benzene, toluene, xylene, n-hexane, cyclohexane, n-pentane, n-heptane and the like. Suitable acid catalyst can be selected from the group comprising of organic or inorganic acids, for example hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, (±) camphor sulphonic acid and the like or mixtures thereof. Suitable bases can be selected from the group comprising of alkali and alkaline earth metal hydroxides, carbonates and bicarbonates. Examples of suitable bases are sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like or mixtures thereof.
A second aspect of the present invention provides a process for the preparation of ether derivative of dihydroartemesinin of the Formula I,
(Formula Removed)
Formula I
wherein R represents aikyl, aryl or aralkyl, said process comprises of, a) treating dihydroartemesinin of Formula II,
(Formula Removed)
Formula II
with dialkyl carbonate of Formula C(O)(OR1)2 wherein R1 represents lower alkyl group, in the
presence of an acid catalyst,
b) isolating the ether derivative of dihydroartemesinin of Formula I from the reaction mass thereof.
Dihydroartemesinin of Formula II can be prepared by reduction of artemesinin by methods known in the art or as exemplified in the present patent application. To a stirred solution of
dihydroartemesinin in a suitable organic solvent is added dialkyl carbonate of Formula C(O)(OR1)2 wherein R1 represents lower alkyl group, followed by an acid catalyst at about 0 to about 15°C. The reaction mixture is stirred for about 1 to about 5 hours and the reaction progress monitored by Thin Layer Chromatography. After completion of the reaction the pH of the mixture is adjusted to about 7.0 to about 8.0 with a base at about 0 to about 15°C. The resultant mixture is suitably worked up to obtain a mixture of p and a isomers of the ether derivative of dihydroartemesinin of Formula I in a ratio of about 70-80 : 30-20. From the mixture of p and a isomer so obtained, pure p-ether derivative of dihydroartemesinin Formula I is obtained by recrystallization from a suitable hydrocarbon solvent.
Suitable organic solvents, hydrocarbon solvents, acid catalyst and bases have already been disclosed in the first aspect of the present invention.
A third aspect of the present invention provides a process for the preparation of ether derivative of dihydroartemesinin of the Formula I(C),
(Formula Removed)
Formula I
wherein R2 represents methyl, aryl or aralkyl, said process comprises of, a) treating dihydroartemesinin of Formula II,
(Formula Removed)
Formula II
with trialkyl orthoformate of the formula HC(OR1)3 wherein R1 represents lower alkyl group, in the presence of an acid catalyst,
b) isolating the ether derivative of dihydroartemesinin of Formula la from the reaction mass thereof,
Dihydroartemesinin of Formula II can be prepared by reduction of artemesinin by methods known in the art or as exemplified in the present patent application. To a stirred solution of dihydroartemesinin in a suitable organic solvent is added trialkyl orthoformate of Formula HC(OR1)3 wherein R1 represents lower alkyl group, followed by an acid catalyst at about 0 to about 15°C. The reaction mixture is stirred for about 1 to about 5 hours and the reaction progress monitored by Thin Layer Chromatography. After completion of the reaction the pH of the mixture is adjusted to about 7.0 to about 8.0 with a base at about 0 to about 15°C. The resultant mixture is suitably worked up to obtain a mixture of (3 and a isomers of the ether derivative of dihydroartemesinin of Formula I in a ratio of about 70-80 : 30-20. From the mixture of p and a isomer so obtained, pure (3-ether derivative of dihydroartemesinin of Formula I is obtained by recrystallization from a suitable hydrocarbon solvent.
Suitable organic solvents, hydrocarbon solvents, acid catalyst and bases have already been disclosed in the first aspect of the present invention.
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 1
Step a) Preparation of dihydroartemesinin
To a stirred suspension of artemisinin (100 g) in methanol (500 ml) maintained at 5-10°C was added sodium borohydride (13.4 g) over 1 hour. The reaction mixture was stirred at 5-10°C for 2 hours and the reaction progress was monitored by thin layer Chromatography. After completion of the reaction, the pH of the mixture was adjusted to 5.5-6.5 using glacial acetic acid at 5-10°C. The reaction mixture was stirred for 30 minutes at 5-10°C and then poured into a mixture of dichloromethane (1200 ml) and deionized water (1000 ml) at 5-10°C. The resultant mixture was stirred for 30 minutes and the aqueous layer was separated. The organic layer was washed with deionized water (1000 ml), concentrated under vacuum to the residual volume (500 ml) at 35 -40°C and employed as such in the next step.
Step b) Preparation of ß-artemether
To a stirred solution of the product of step a) in dichloromethane (500 ml) was added trimethyl orthoformate (400 ml) followed by p-toluenesulphonic acid (5 g) at 5-10°C. The reaction mixture was stirred for 3 hours and the reaction progress was monitored by thin layer chromatography. After completion of reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5%) at 5-10°C and deionized water (200 ml) was added. The resultant mixture was stirred for 30 minutes and the organic layer was separated, washed with deionized water (200 ml), dried over anhydrous sodium sulphate and concentrated under vacuum at 35-38°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (150 ml) and the solid thus obtained was recrystallized from n-pentane (100 ml) at -10 to -5°C to afford the title compound. Yield: 45 g
EXAMPLE 2 Preparation of ß-artemether
To a stirred suspension of dihydroartemisinin (5 g) in toluene (50 ml) at 5-10°C was added trimethyl orthoformate (20 ml) followed by p-toluenesulphonic acid (0.25 g). The reaction mixture was stirred at 5-10°C for 2 hour and monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5%) at 5-10°C and deionized water (25 ml) was added The resultant mixture was stirred for 30 minutes and the layers were separated. The organic layer was washed with deionized water (25 ml), dried over anhydrous sodium sulphate and concentrated completely under vacuum at 35-45°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (10 ml) and the solid thus obtained was recrystallized from n-pentane (5 ml) at -10 to -5°C to afford the title compound. Yield: 2.15g
EXAMPLE 3
Preparation of ß-artemether
To a stirred suspension of dihydroartemisinin (5 g) in hexanes (50 ml) at 5-10°C was added trimethyl orthoformate (20 ml) followed by p-toluenesulphonic acid (0.25 g). The reaction mixture was stirred at 5-10°C for 2 hour and monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5 %) at 5-10°C and deionized water (25 ml) was added. The resultant mixture was stirred for 30 minutes and the layers were separated. The organic layer was washed with deionized water (25 ml), dried over anhydrous sodium sulphate and concentrated completely
under vacuum at 35-45°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (10 ml) and the solid thus obtained was recrystallized from n-pentane (5 ml) at -10 to -5°C to afford the title compound. Yield: 2.2 g.
EXAMPLE 4
Step a) Preparation of dihydroartemesinin
To a stirred suspension of artemisinin (100 g) in methanol (500 ml) maintained at 5-10°C was added sodium borohydride (13.4 g) over 1 hour. The reaction mixture was stirred at 5- 10°C for 2 hours and the reaction progress was monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 5.5-6.5 using glacial acetic acid at 5-10°C. The resultant mixture was stirred for 30 minutes at 5-10°C and poured under stirring into a mixture of dichloromethane (1200 ml) and deionized water (1000 ml) at 5-10°C. The resultant mixture was stirred for 30 minutes and the aqueous layer was separated. The organic layer was washed with deionized water (1000 ml), concentrated under vacuum to the residual volume (500 ml) at 35 - 40°C and employed as such in the next step.
Step b) Preparation of ß-artemether
To a stirred solution of the product of step a) in dichloromethane (500 ml) was added trimethyl borate (200 ml), followed by p-toluenesulphonic acid (5 g) at 5-10°C. The reaction mixture was stirred for 3 hours and the reaction progress was monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5 %) at 5-10°C and deionized water (200 ml) was added. The resultant mixture was stirred for 30 minutes and the organic layer was separated and washed with deionized water (200 ml), dried over anhydrous sodium sulphate and concentrated under vacuum at 35-38°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (150 ml) and the solid thus obtained was recrystallized from n-pentane (100 ml) at -10 to -5°C to afford the title compound. Yield: 41 5 g
EXAMPLE 5
Preparation of ß-artemether
To a stirred suspension of dihydroartemisinin (5 g) in dichloromethane (50 ml) at 5-10°C was added trimethyl borate (10 ml) followed by p-toluenesulphonic acid (0.5 g). The reaction mixture was stirred at 5-10°C for 2 hours and monitored by thin layer chromatography. After completion of
the reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5 %) at 5-10°C and deionized water (50 ml) was added. The resultant mixture was stirred for 30 minutes and the layers were separated. The organic layer was washed with deionized water (50 ml), dried over anhydrous sodium sulphate and concentrated completely under vacuum at 35-45°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (5 ml) and the solid thus obtained was recrystallized from n-pentane (5 ml) at -10 to -5°C to afford the title compound. Yield: 2.1 g
EXAMPLE 6
Step a) Preparation of dihydroartemesinin
To a stirred suspension of artemisinin (100 g) in methanol (500 ml) maintained at 5-10°C was added sodium borohydride (13.4 g) over 1 hour. The reaction mixture was stirred at 5-10°C for 2 hours and the reaction progress was monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 5.5-6.5 using glacial acetic acid at 5-10°C. After stirring for 30 minutes at 5-10°C the mixture was poured under stirring into a mixture of dichloromethane (1200 ml) and deionized water (1000 ml) at 5-10°C. The resultant mixture was stirred for 30 minutes and the aqueous layer was separated. The organic layer was washed with deionized water (1000 ml), concentrated under vacuum to the residual volume (500 ml) at 35 -40°C and employed as such in the next step.
Step b) Preparation of ß-artemether
To a stirred solution of the product of step a) in dichloromethane (500 ml) was added dimethyl carbonate (200 ml), followed by p-toluenesulphonic acid (5 g) at 5-10°C. The reaction mixture was stirred for 3 hours and the reaction progress monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 7.0- 8.0 using aqueous sodium bicarbonate solution (5 %) at 5-10°C and deionized water (200 ml) was added. The resultant mixture was stirred for 30 minutes and the organic layer was separated and washed with deionized water (200 ml), dried over anhydrous sodium sulphate and concentrated under vacuum at 35-38°C to obtain a residue which contained p and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (150 ml) and the solid thus obtained was recrystallized from n-pentane (100 ml) at -10 to -5°C to afford the title compound. Yield: 40 g
EXAMPLE 7
Preparation of ß-artemether
To a stirred suspension of dihydroartemisinin (5 g) in dichloromethane (50 ml) maintained at 5-10°C was added dimethyl carbonate (10 ml) followed by p-toluenesulphonic acid (0.5 g). The reaction mixture was stirred at 5-10°C for 20 hours and the reaction progress monitored by thin layer chromatography. After completion of the reaction, the pH of the mixture was adjusted to 7.0-8.0 using aqueous sodium bicarbonate solution (5 %) at 5-10°C and deionized water (25 ml) was added. The resultant mixture was stirred for 30 minutes and the layers were separated. The organic layer was washed with deionized water (25 ml), dried over anhydrous sodium sulphate and concentrated completely under vacuum at 35-45°C to obtain a residue which contained (3 and a isomers of artemether in a ratio of 75-80 : 25-20. The residue was crystallized from hexanes (10 ml) and the solid thus obtained was recrystallized from n-pentane (5 ml) at -10 to -5°C to afford the title compound. Yield: 2.4 g

WE CLAIM:
1. A process for the preparation of ether derivative of dihydroartemesinin of the Formula I,
(Formula Removed)
Formula I
wherein R represents alkyl, aryl or aralkyl, said process comprises of, a) treating dihydroartemesinin of Formula II,
(Formula Removed)
Formula II
with trialkyl borate of the formula B(OR1)3 wherein R1 represents lower alkyl group, in the
presence of an acid catalyst,
b) isolating the ether derivative of dihydroartemesinin of Formula I from the reaction mass thereof.
2. A process for the preparation of ether derivative of dihydroartemesinin of the Formula I,
(Formula Removed)
Formula I
wherein R represents alkyl, aryl or aralkyl, said process comprises of, a) treating dihydroartemesinin of Formula II,
(Formula Removed)
Formula II
with dialkyl carbonate of Formula C(O)(OR1)2 wherein R1 represents lower alkyl group, in the
presence of an acid catalyst,
b) isolating ether derivative of dihydroartemesinin of Formula I from the reaction mass thereof.
3. A process for the preparation of ether derivative of dihydroartemesinin of the Formula I(C),
(Formula Removed)
Formula I
wherein R2 represents methyl, aryl or aralkyl, said process comprises of, a) treating dihydroartemesinin of Formula II,
(Formula Removed)
Formula II
with trialkyl orthoformate of Formula HC(OR1)3 wherein R1 represents lower alkyl group, in the
presence of an acid catalyst,
b) isolating the ether derivative of dihydroartemesinin of Formula I from the reaction mass thereof.
4. A process according to claims 1, 2 and 3 wherein the acid catalyst is selected from the group comprising of organic or inorganic acids or mixtures thereof.
5. A process according to claims 1, 2 and 3 wherein step a) is carried out in the presence of an
organic solvent.
6. A process according to claim 5 wherein the organic solvent is selected from the group
comprising of chlorinated hydrocarbons, hydrocarbons, polar aprotic solvents or mixtures thereof.
7. A process according to claims 1, 2 and 3 further comprising of obtaining the p-isomer of the
ether derivative of dihydroartemesinin of Formula I, by recrystallization from a suitable solvent.
8. A process according to claim 7 wherein the solvent is selected from hydrocarbons or mixtures
thereof.
9. A process according to claim 8 wherein the solvent is selected from the group comprising of n-
hexane, n-pentane, n-heptane, cyclohexane or mixtures thereof.
10. A process according to claims 1 and 2 wherein R represents methyl or ethyl.