Field of the Invention
The present invention relates to simple and cost-effective process for the preparation of ether derivatives of dihydroartemisinin. The present invention enables preparation of pure p-ether derivatives of dihydroartemisinin which are well-known antimalarial agents.
Background of the Invention
Dihydroartemisinin is derived from artemisinin, which is a sesquiterpene lactone isolated from Chinese-Vietnamese plant Artemesia annua L. Of the ether derivatives of dihydroartemisinin represented by Formula I,
wherein R can be alkyl, aryl or aralkyl, the ß-alkyl ether derivatives viz., artemether of Formula l(A) and arteether of Formula 1(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)
Coartem® (Artemether + Lumefantrine), a fixed dose combination of two active ingredients, artemether and lumefantrine (a synthetic racemic fluorene derivative) is indicated in artemisinin-based combination therapy (ACT) used to treat malaria including the stand by-emerging treatment of adults and children with infections due to P. falciparum or mixed infections including P. falciparum-the deadliest form of the disease. The combination has gametocytocidal action.
P.falciparum and p.virax are the two dominant species with relative frequency of 60% and 40% respectively. However, this proportion varies from place to place and from season to season. In malaria epidemic situations, P. falciparum is the dominant parasite species and almost all malarial deaths happen due to infections by this species. Moreover, the biological diversity of P. falciparum, its ability to develop resistance to a number of anti-malarial drugs has been a major challenge in malaria chemotherapy.
Brossi et. a/., J. Med. Chem. 31, 646-649 (1988) disclose a process for the preparation of arteether by treating a solution of dihydroartemisinin 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. a/., J. Nat. Prod. 55, 878-883 (1992) disclose a process for the preparation of arteether by treating a solution of anhydrodihydroartemisinin in absolute alcohol with p-toluenesulphonic acid. The process requires large amounts of the Lewis acid catalyst and the p-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 dihydroartemisinin 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.
US Patent No. 6,683,193 (herein after the '193 patent) discloses a one-pot process for the preparation of artemether from artemisinin wherein artemisinin is reduced to dihydroartemisinin in methanol solvent and in the same solvent dihydroartemisinin 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.
Summary of the Invention
The present inventors have developed a robust and cost effective process for the preparation of ether derivatives of dihydroartemisinin. The present process is carried out in the absence of solvent and affords pure p-artemether without employing tedious and time consuming column chromatographic purification.
A first aspect of the present invention provides a process for the preparation of ether derivative of dihydroartemisinin of the Formula I,
(Formula Removed)
wherein R represents alkyl, aryl or aralkyl, said process comprises of,
a) treating dihydroartemisinin of Formula II,
(Formula Removed)
with etherifying agent in the absence of solvent,
b) isolating the ether derivative of dihydroartemisinin of Formula I from the reaction mass
thereof.
The process of the present invention may involve one or more of the following embodiments. For example, in one embodiment, the etherifying agent is selected from the group comprising of trialkylborates, trialkyl orthoformates, dialkyl carbonates or mixtures thereof. In another embodiment trialkyl orthoformate is selected from the group comprising of trimethyl orthoformate or triethyl orthoformate. In another embodiment, the reaction in step a) is performed in the presence of an acid catalyst selected from the group comprising of organic or inorganic acids or mixtures thereof. In another embodiment, the reaction in step a) is carried out in the presence of catalytic amount of water. In yet another embodiment, the pure p-isomer of the ether derivative of dihydroartemisinin of Formula I is obtained by recrystallization from a suitable solvent selected from the group comprising of benzene, toluene, xylene, n-hexane, cyclohexane, n-pentane, n-heptane or mixtures thereof. In yet another embodiment, R is alkyl such as methyl or ethyl.
Detailed Description of the Invention
The present invention provides a process for the preparation of ether derivative of dihydroartemisinin of the Formula I,
(Formula Removed)
wherein R represents alkyl, aryl or aralkyl, said process comprises of,
a) treating dihydroartemisinin of Formula II,
(Formula Removed)
with etherifying agent in the absence of solvent,
b) isolating the ether derivative of dihydroartemisinin of Formula I from the reaction mass
thereof.
Dihydroartemisinin of Formula II can be prepared by reduction of artemisinin by methods known in the art or as exemplified in the present patent application. To a stirred mixture of dihydroartemisinin of Formula II in etherifying agent at about 5-15°C, was added acid catalyst and optionally water. The reaction progress was monitored by High Performance Liquid Chromatography. After completion of the reaction, the mixture was quenched using a base. The quenched mixture was extracted with a suitable organic solvent. The organic layer was treated with activated carbon and the mixture filtered over hyflo. The filtrate was concentrated and traces of organic solvent were removed using methanol under vacuum. The resultant mass was charged with water and stirred for about 1-2 hours. The solid so obtained was filtered, washed with aqueous methanol (50%) and dried to obtain the desired ether derivative of dihydroartemisinin of Formula I in crude form. From the crude compound, pure p-ether derivative of dihydroartemisinin of Formula I was obtained by recrystallization from a hydrocarbon solvent.
Suitable etherifying agent can be selected from the group comprising of trialkylborates, trialkyl orthoformates, dialkyl carbonates and the like or mixtures thereof. The trialkylborates can be selected from the group comprising of trimethylborate, triethylborate and the like. The trialkyl orthoformates can be selected from the group comprising of trimethyl orthoformate, triethyl orthoformate and the like. The dialkyl carbonates can be selected from the group comprising of dimethyl carbonate, diethyl carbonate and the like.
Suitable acid catalyst can be selected from the group comprising of organic or inorganic acids such as 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.
Suitable organic solvent can be selected from the group comprising of halogenated hydrocarbons, esters, hydrocarbon solvents and the like or mixtures thereof. The halogenated hydrocarbons can be selected from the group comprising of dichloromethane, dichloroethane, carbon tetrachloride, chloroform and the like or mixtures thereof. The esters can be selected from the group comprising of ethyl acetate, methyl formate, methyl acetate, n-butyl acetate, isobutyl acetate and the like or mixtures thereof. The hydrocarbon solvents can be selected from the group comprising of benzene, toluene, xylene, n-hexane, cyclohexane, n-pentane, n-heptane and the like or mixtures thereof.
The term "pure" as used herein signifies purity of 99% or more. Preferably the purity is 99.5% or more. More preferably the purity is 99.9% or more.
The term "alkyl" as used herein refers to optionally substituted C1-C6 straight or branched hydrocarbon such as methyl, ethyl or propyl. The optional substituent can be selected from the group comprising of hydroxyl, halogen, alkoxy.
The term "aryl" as used herein refers to optionally substituted aromatic C6-C10 hydrocarbon such as phenyl or naphthyl. The optional substituent can be a simple aromatic substituent such as alkyl, alkoxy, hydroxyl, halogen, cyano or amino.
The term "aralkyl" as used herein refers to optionally substituted C1-C6 alkyl-aromatic C6-C10 hydrocarbon such as benzyl or phenethyl. The optional substituents can be a simple aromatic substituent such as alkyl, alkoxy, hydroxyl, halogen, cyano or amino.
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 dihydroartemisinin
To a stirred mixture of artemisinin (200 g) in methanol (140 ml) at 0-5°C was added sodium borohydride (32.16 g) over 1 hour. The reaction mixture was stirred at 0-5°C for (2 hours) and maintained at the same temperature for 2 hours. After completion of the reaction, the mixture was quenched using dilute acetic acid in methanol (200 ml, 30%). To the quenched mixture deionized water (3200 ml) was added. The solid so obtained was filtered and dried to afford the title compound which is a mixture of a- and p-isomers, as a white crystalline powder. Yield: (190 g; 94%) Purity: 99.77% (by HPLC)
Step b) Preparation of p-artemether
To a stirred mixture of dihydroartemisinin (95 g) in trimethyl orthoformate (285 ml) at 5-10°C was added water (13.3 ml) and p-toluenesulphonic acid (4.75 g). The reaction progress was monitored by High Performance Liquid Chromatography. After completion of reaction, the mixture was quenched with aqueous sodium bicarbonate solution (5%). The quenched mixture was extracted in dichloromethane. The dichloromethane layer was treated with activated carbon and the treated organic layer was filtered over hyflo. The filtrate was concentrated under vacuum and traces of dichloromethane were removed using methanol under vacuum till the residual volume was 300ml. To the concentrated mixture water (143 ml) was added dropwise at 20-30°C and the resultant mixture was stirred for 1 hour. The solid so obtained was filtered, washed with aqueous methanol (50%) and dried to afford the title compound as a white crystalline powder. Yield: (70 g; 70%) Purity: 99.02% (by HPLC)
Step c) Preparation of pure p-artemether
The crude compound obtained in Step b) was recrystallized from n-hexane (175 ml) to afford the title compound. Yield: (58 g; 83%) Purity: 99.95% (by HPLC)

WE CLAIM:
1. A process for the preparation of ether derivative of dihydroartemisinin of the Formula I,
(Formula Removed)
wherein R represents alkyl, aryl or aralkyl, said process comprises of,
a) treating dihydroartemisinin of Formula II,
(Formula Removed)
with etherifying agent in the absence of solvent,
b) isolating the ether derivative of dihydroartemisinin of Formula I from the reaction mass
thereof.
2. The process according to claim 1 wherein the etherifying agent is selected from the group comprising of trialkylborates, trialkyl orthoformates, dialkyl carbonates or mixtures thereof.
3. The process according to claim 2 wherein the trialkyl orthoformate is selected from the group comprising of trimethyl orthoformate, triethyl orthoformate.
4. The process according to claim 3 wherein the trialkyl orthoformate is trimethyl orthoformate.
5. The process according to claim 1 wherein step a) is performed in the presence of an acid catalyst.
6. The process according to claim 5 wherein the acid catalyst is selected from the group comprising of organic or inorganic acids or mixtures thereof.
7. The process according to claim 1 wherein step a) is carried out in the presence of catalytic amount of water.
8. The process according to claim 1 further comprising of obtaining pure p-isomer of the ether derivative of dihydroartemisinin of Formula I by recrystallization from a suitable solvent.
9. The process according to claim 8 wherein the solvent is selected from the group comprising of benzene, toluene, xylene, n-hexane, cyclohexane, n-pentane, n-heptane or mixtures thereof.
10. A process according to claims 1 and 2 wherein R is alkyl selected from methyl or ethyl.