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 P-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 at 70°C. Arteether is purified by hexane crystalisation and further separation from the concentrated filterate by column chromatography. This process is carried out at high temperature of 70°C and a separate crystallisation is needed to isolate p-arteether. This process also forms a-isomer which is separated by column chromatography.

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 0-arteether obtained as the product is contaminated with the Cu-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 a-and P-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 a- and P-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 AlC13 as catalyst. The product is obtained as a mixture of a- and p- isomers in the ratio of 29.6:71.4.

Organic process research and development 2007, 11(3), 336-340, describes a process for the etherification of dihydroartemisinin at 28-30°C to obtain crude artemether which is further purified using methanol and water.

WO2009109989 discloses a process of preparation of ethers of dihydroartemisinin in which dihydroartemisinin is reacted with an alcohol in trialkylorthoformate, 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.

Our co-pending application IN2823CHE2010 describes a process for the preparation of artemether in which the etherification of dihydroartemisinin is carried out at 20°C to obtain a crude artemether which is isolated and further purified to obtain pure p-artemether. This process still forms 4-5% of a-artemether and needs a further purification.
Thus most of the processes mentioned in the prior art suffer from drawbacks such as use of column chromatography in the separation of desired P-isomer. Moreover, the etherification of dihydroartemisinin is carried out at high temperature ranging from 20 to 70°C which leads to formation of unwanted impurities as well as a-isomer. These processes further involve isolation of crude artemether and a separate purification to obtain p-isomer. This leads to loss of material as well as generation of high volume of effluent and prolonged reaction time cycle.

Thus there is a need to develop a process which avoids purification and formation of a-isomer and also reduces the reaction time cycle. The inventors of the present invention have surprisingly found that p-isomer of ethers of dihydroartemisinin can be obtained in a high yield and high purity without involving a separate purification.

SUMMARY OF THE INVENTION

Accordingly, the main aspect of the invention is to provide a process for the preparation of ethers of dihydroartemisinin free from their a-isomers comprising reacting dihydroartemisinin with trialkylorthoacetate and a catalytic amount of mineral acid at low temperature, in presence of an alcoholic solvent where invention lies in carrying out the reaction in about 4 to 5 volume of solvent at a temperature in the range of 0 to 5°C and precipitating the formed artemether with a controlled amount of water.

The another aspect of the invention is to provide a novel crystalline form of artemether substantially same as given in figure 1 and characterised by having unique XRPD peaks at 20 values 26.264, 28.344, 31.928, 32.974 and 48.461±0.2.

The another aspect of the invention is to provide another novel crystalline form of artemether substantially same as given in figure 2 and

characterised by having unique XRPD peaks at 20 values 10.996, 12.279, 12.809, 13.823, 15.584,17.131, 18.168, 25.042 and 25.769±0.2.

DESCRIPTION OF THE DRAWINGS

Figure 1: X-Ray diffractogram of Artemether of the present invention obtained according to example 1

Figure 2: X-Ray diffractogram of Artemether after melting and drying obtained according to example 2

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 is reacted with trialkylorthoacetate in the presence of an alcoholic solvent. The alcoholic solvent for the reaction may be selected from methanol or ethanol and used 4 to 5 volumes with respect to dihydroartemisinin. 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. The reaction of dihydroartemisinin with trialkylorthoacetate is carried out at a temperature in the range of -2 to 10°C preferably -2 to 5°C and more preferably 0 to 5°C.

The precipitation of the product is carried out with the addition of controlled amount of water preferably by adding 4-6 volumes of water with respect to dihydroartemisinin input. The reaction at low temperature avoids the formation of many unwanted impurities as well as unwanted a-isomer.

The reaction is preferably carried out in presence of trialkylorthoacetate with volume equal to that of dihydroartemisinin.

In another embodiment of the invention the crystal form of artemether obtained by the present invention is novel and substantially same as given in figure 1 and characterised by having unique XRPD peaks at 29 values 26.264, 28.344, 31.928, 32.974 and 48.461±0.2.

In another embodiment of the invention artemether obtained by the present invention is melted and cooled slowly to crystallise to obtain a novel crystalline form of artemether substantially same as given in figure 2 and characterised by having unique XRPD peaks at 2© values 10.996, 12.279, 12.809, 13.823, 15.584, 17.131, 18.168, 25.042 and 25.769±0.2.

The process of the present invention obviates a separate purification step which almost necessary in prior art processes. This saves 10 to 15% loss of material associated with purification. The material lost during purification can't be recovered due to very sensitive nature of the product.

Some of the salient advantages of the present invention are as give below:

a) The artemether obtained by the present invention is free from a-artemether.

b) Since the reaction is carried out at low temperature the formation of impurities are reduced drastically and provides highly pure artemether.

c) The present process reduces significantly the reaction time.

d) The present invention obviates separate purification which in turn obviates crude isolation and increases the yield and reduces the effluent generation.

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 (500 mL) and trimethylorthoacetate (100 mL) was stirred and the reaction mass was cooled to 0 to 2°C. A mixture of 0.36 mL 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. The reaction was heated to 40±2°C. The product was filtered through hyflow bed and the bed was washed with hot methanol. The filtrate was charged slowly with 450 mL of water and stirred. The filtrate was cooled to 25-30°C and further cooled to 5±2°C and maintained for some time. The product was filtered and washed with water (100 mL), suck dried and further dried at 30±2°C till moisture content comes to 0.5%.

Yield: 94 g

Example 2: Crystallisation of Artemether by heating and cooling

Artemisinin was taken in a RB flask under inert atmosphere and heated to 80-85°C to get a melted solution. The melted solution was poured in to a Petridish under inert atmosphere and kept in a desiccator for cooling. The obtained crystals were dried under vacuum at 40 °C.

We claim:

1. A process for the preparation of ethers of dihydroartemisinin free from their a-isomers comprising reacting dihydroartemisinin with trialkylorthoacetate and a catalytic amount of mineral acid at low temperature, in presence of an alcoholic solvent where invention lies in carrying out the reaction in about 4 to 5 volume of solvent at a temperature in the range of 0 to 5°C and precipitating the formed artemether with a controlled amount of water.

2. A process according to claim 1 wherein, the ethers of dihydroartemisinin are artemether or arteether.

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

4. 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.

5. A process according to claim 1 wherein, the reaction is terminated by the addition of base selected from the group consisting sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

6. A process according to claim 4, wherein the base is sodium bicarbonate.

7. A process according to claim 1, wherein the controlled amount of water for precipitation varies in the range of 4-6 volumes with respect to dihydroartemisinin input.

8. A crystalline form of artemether substantially same as given in figure 1 and characterised by having unique XRPD peaks at 20 values 26.264, 28.344, 31.928, 32.974 and 48.461±0.2.

9. A crystalline form of artemether substantially same as given in figure 2 and characterised by having unique XRPD peaks at 2G values 10.996, 12.279, 12.809, 13.823, 15.584, 17.131, 18.168, 25.042 and 25.769±0.2.