FIELD OF INVENTION

The present invention relates to a facile and cost-effective process for the preparation of ether derivatives of dihydroartemisinin. The present invention further enables preparation of pure β-ether derivatives of dihydroartemisinin, commonly known as Artemether, the methyl ether derivative and Arteether, the ethyl ether derivative, which are well-known antimalarial agents.

BACKGROUND OF THE INVENTION

Artemether of Formula I and Arteether of Formula II have been extensively studied and found to be effective in the treatment of malaria including uncomplicated/severely complicated/cerebral and multi-drug resistant malaria.

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.

P. falciparum and P. vivax 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. al., J. Med Chem. 31, 645-650 (1988) disclose a process for the preparation of arteether by treating a solution of dihydroartemisinin with BF3-etherate in benzene and ethanol. Arteether is purified by hexane crystalisation and further separation from the concentrated filterate by column chromatography. Brossi et.al also reported an epimerisation of α-arteether into β-arteether by treating a solution of α-arteether in benzene with ethanol and BF3-etherate at reflux temperature. This process apart from hexane crystallisation uses column chromatography for the isolation of β-arteether as well as it uses carcinogenic solvent benzene for epimerisation.

EL-Feraly et. al., 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 β-arteether obtained as the product is contaminated with the C11-epimer and further purification needs to be carried out.

Bhakuni et. al., Indian J. Chemistry, 34(B), 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 using chlorotrimethylsilane as acid catalyst. This process uses column chromatography to obtain pure Artemether from product mixture.

US Patent No. 6,683,193 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. This process leads to greater amounts of impurities in the desired product and α-and  β-Artemether  obtained  are  separated  and  purified  by  column chromatography.

Lin et al. in J. Med Chem., 1995, 38, 764-770, discloses the preparation of Arteether from dihydroartemisinin in anhydrous ether and alcohol using boron trifluoride etherate as the acid catalyst. Yield of purified product was in the range of 40-90% wherein the purification of the Arteether was carried out by column chromatography.

IN 192961 describes a process for the preparation of arteether by reacting dihydroartemisinin with trialkyl ortho formate in the presence of a solid acid catalyst. The product is obtained as a mixture of α- and β-isomers in the ratio of 30:70.

Indian patent application 00542/DEL/2003 describes a process for the preparation of arteether by reacting dihydroartemisinin with dry ethanol in toluene at 50-60° C for 15 min. using anhydrous AICI3 as catalyst. The product is obtained as a mixture of α- and β- isomers in the ratio of 29.6:71.4.

Organic process research and development 2007, 11(3), 336-340, describes use of hydrochloric acid as acid catalyst.

WO2009109989 discloses a process of preparation of ethers of dihydroartemisinin in which dihydroartemisinin is reacted with an alcohol in trial kylorthoformate, 2-methoxy propene, 2,2-dimethoxypropane etc in presence of pro acids like acetyl chloride, methane sulphonyl chloride, thionyl chloride etc. The maximum yield obtained in this process after purification is 74.67%. Moreover, it uses pro-acid which is further converted to acid in-situ.

Thus most of the processes mentioned in the prior art suffer from draw-backs such as use of column chromatography in the separation of desired β-isomer. Secondly Artemether obtained by the use of p-toluenesulphonic acid contains some unknown impurity which is difficult to remove. The prior art process uses carcinogenic solvent like benzene, costly reagent like BF3-etherate for epimerisation.

Thus there is a need to develop a facile and economical process which will give β-isomer of ethers of dihydroartemisinin in high purity and high yield. The inventors of the present invention have surprisingly found that β-isomer of ethers of dihydroartemisinin can be obtained in a high yield and high purity by reacting dihydroartemisinin with trialkylorthoacetate in presence of catalytic amount of an acid and in presence or absence of an alcohol.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a novel process for the preparation of ethers of dihydroartemisinin, more particularly artemether and arteether having high ratio of desired β-isomer with high yield and purity.

It is another object of the present invention to provide a facile, cost effective and environment friendly process for the preparation of artemether and arteether by which isolation of desired isomer in high yield is very simple.

It is yet another object of the invention to provide a simple process for converting a-isomer of artemether or arteether into their β-isomer which involves simple and cost effective reagent.

SUMMARY OF THE INVENTION

Accordingly, the main aspect of the invention is to provide a process for the preparation of ethers of dihydroartemisinin comprising the steps of:

a) reacting dihydroartemisinin with trial kylorthoacetate and a catalytic amount of mineral acid, in presence or absence of an alcoholic solvent and in absence of an organic pro-acid catalyst;

b) adding aqueous solution of base to quench the reaction and precipitate the product;

c) isolating the obtained compound using a suitable solvent; and

d) recrystalising the product using an aqueous alcoholic solvent to obtain the ethers of dihydroartemisinin.

Another of the invention is to provide a process for the epimerisation of a-ethers of dihydroartemisinin into β- ethers of dihydroartemisinin comprising:

a) reacting α-ethers of dihydroartemisinin with trimethylchlorsilane in toluene;

b) quenching with a solution of base in water;

c) separating organic layer and evaporating the solvent; and

d) purifying the obtained residue with aqueous alcoholic solvent.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the invention, the ethers of dihydroartemisinin comprise methyl ether of dihydroartemisinin called Artemether and ethyl ether of dihydroartemisinin called arteether.

In an embodiment of the invention, the present process doesn"t use any organic pro-acid catalysts such as aliphatic acid halide, aromatic acid halide, and inorganic acid halide or sulfonyl chloride, instead it uses a readily available mineral acid selected from the group consisting of sulphuric acid, phosphoric acid, anhydrous hydrochloric acid and alcoholic hydrochloric acid, preferably sulphuric acid as a catalyst for the reaction of dihydroartemisinin with trialkylorthoacetate.

In another embodiment of the invention, the dihydroartemisinin can be reacted with trialkylorthoacetate in the presence or in the absence of an alcoholic solvent.  The alcoholic solvent for the reaction may be selected from methanol or ethanol. The reagent trialkylorthoacetate is preferably trimethylorthoacetate or triethylorthoacetate. The use of trialkylorthoacetate in absence of an acid pro-acid catalyst significantly reduces the quantity of acid catalyst required and the time needed for the completion of reaction. The selection of the alcoholic solvent and trialkylorthoacetate may be selected depending on the ester of dihydroartemisinin to be formed.

In yet another embodiment of the present invention, the product is isolated by easy work up procedure wherein the reaction mass after treating with a solution of the base in water where the base is selected from the group consisting sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate, is added below 20°C. The suitable solvent for the isolation is selected from water, a ketonic solvent such as acetone, MIBK etc. or a mixture thereof, preferably water. The precipitated product is filtered and stirred with water to obtain crude ethers of dihydroartemisinin. The obtained crude ethers are recrystalised from a mixture of alcohol preferably methanol and water to get a highly pure β-isomer.

In yet another embodiment of the present invention the epimerisation of α-ethers of dihydroartemisinin into β-ethers of dihydroartemisinin is carried out using trimethylchlorsilane in toluene. The present invention avoids the use of carcinogenic solvent benzene and uses a very simple and cost-effective reagent trimethylchlorsilane. α-Ethers of dihydroartemisinin are reacted with trimethylchlorsilane in toluene at 20 C-40°C preferably at 25°C-30°C. The reaction is carried out for 10 to 15 hours preferably for about 12 hours. The base for quenching is selected from alkali metal carbonates or bicarbonates preferably it is sodium bicarbonate. The obtained material is further purified by water and an alcoholic solvent preferably methanol.

In yet another embodiment of the invention Artemether obtained above is mixed with an alcoholic solvent preferably methanol at 25°C to 35°C, preferably at 30°C and heated to 40°C. The reaction mass is filtered hot and washed with hot methanol. Water was added to hot filtrate. The reaction mass is optionally seeded with pure β-Artemether in lots. Further water is charged into it and the reaction mass is cooled to 5-10°C, filtered, washed with chilled solution of methanol in water and suck dried.

The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.

Example 1: Preparation of artemether

Dihydroartemisinin (100 g) in methanol (300 mL) and trimethylorthoacetate (200 mL) was stirred and the reaction mass was cooled to 20°C. A mixture of 0.6896 g of concentrated sulphuric acid in 40 ml of methanol was added to the reaction mass. After completion of the reaction a solution of 8.4g of sodium bicarbonate in 100 ml water was added to terminate the reaction. Afterwards 1150 ml of water was added to the reaction mixture below 20°C to precipitate out the crude artemether. The suspension was stirred at 20°C for one hour, filtered, washed with 100 ml of water and suck dried. The so obtained artemether was stirred with 1000ml of water at 25°C for one hour, filtered, washed and suck dried to get crude artemether.
Dry weight 98.4g

Example 2: Preparation of artemether
Dihydroartemisinin (l00g) and 400ml trimethylorthoacetate were cooled to 20(±2)°C. Cone. H2S04 (0.36 ml) was added to the above reaction mass at 20(±2)°C and stirred for an hour. A solution of sodium bicarbonate (8.4g in 100 ml water) was added slowly between 15 and 20°C and stirred for 15 minutes. Afterwards 1150 ml of water was added slowly over a temperature range of 15 and 20°C and stirred for an hour. The product was filtered, washed with DM water (100 ml) and suck dried. The obtained product was pulped with 1000 ml of DM water at ambient temperature, filtered, washed the solids with 100 ml of DM water and suck dried.
Weight of the wet product: 111g

Example 3: Process for purification of artemether
Α-Artemether (1.12 Kg) and methanol (11.2 L) were mixed at 30±2°C and heated to 40±2°C under stirring for 15 minutes. The reaction mass was filtered hot and washed with methanol (1.4 L). The reaction mass was heated to 40±2°C and DM water (2.38 L) was charged into it slowly while maintaining the temperature at 40±2°C. The reaction mass was seeded with pure p-Artemether (0.0224 Kg) in lots. DM water (9.67 L) was charged into it and the temperature was maintained at 40±2°C for 15 minutes. The reaction mass was cooled to 5-10°C over a period of 2 hours and maintained for 30 minutes. The reaction mass was filtered, washed with chilled 50% solution of methanol in DM water (1.12 L) and suck dried.

Yield: 1 Kg, 85% (w/w)

Example: Epimerisation of a-artemother into β-artemether
a-Artemether (lOg), toluene (50ml) and trimethylchlorsilane (3.64g) were stirred at 25°C-30°C for 12 hours. A solution of sodium bicarbonate (0.84g) in 8.4 ml of water was added and stirred. The layers were separated. The aqueous layer was washed with toluene and toluene layer was washed with water. The organic layers were combined and toluene was distilled under vacuum. The residue was stirred in a mixture of acetone (50 ml) and water 250ml) at 5°C for an hour and filtered to get 9.28 g of wet material. The wet material was stirred in water (160 ml) to remove the inorganic and obtained 8.88g of wet material. This was further purified by water and methanol.

We claim:

1. A process for the preparation of ethers of dihydroartemisinin comprising
the steps of:

a) reacting dihydroartemisinin with trialkylorthoacetate and a catalytic amount of mineral acid, in presence or absence of an alcoholic solvent and in absence of an organic pro-acid catalyst;

b) adding aqueous solution of base to quench the reaction and precipitate the product;

c) isolating the obtained compound using a suitable solvent; and

d) recrystalising the product using an aqueous alcoholic solvent.

2. A process according to claim 1 wherein, trialkylorthoacetate is selected from trimethylorthoacetate and triethylorthoacetate.

3. A process according to claim 1 wherein, mineral acid is selected from the group consisting of sulphuric acid, phosphoric acid, anhydrous hydrochloric acid and alcoholic hydrochloric acid.

4. A process according to claim 1 wherein, the base is selected from the group consisting sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

5. A process according to claim 1 wherein, the base is sodium bicarbonate.

6. A process according to claim 1 wherein, the suitable solvent for isolation is selected from water, acetone, MIBK or its mixture thereof.

7. A process for the epimerisation of a-ethers of dihydroartemisinin into p-ethers of dihydroartemisinin comprising:

a) reacting a-ethers of dihydroartemisinin with trimethylchlorsilane in toluene;

b) quenching with a solution of base in water;

c) separating organic layer and evaporating the solvent; and

d) purifying the obtained residue with aqueous alcoholic solvent.

8. A process according to claim 1 or 7 wherein, the ethers of dihydroartemisinin comprise methyl ether of dihydroartemisinin and ethyl ether of dihydroartemisinin.

9. A process according to claim 7 wherein, the base is selected from the group consisting sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

10. A process according to claim 7 wherein, the base is sodium bicarbonate.