WO2009109989A1

WO2009109989A1 - A novel process for the preparation of ethers of dihydroartemisinin

Info

Publication number: WO2009109989A1
Application number: PCT/IN2009/000050
Authority: WO
Inventors: Chintamani Prabhakar Bapat; Sushil Joginderpal Dheer; Somnath Kisan Dhamale
Original assignee: Calyx Chemicals and Pharmaceuticals Ltd
Current assignee: Calyx Chemicals and Pharmaceuticals Ltd
Priority date: 2008-01-21
Filing date: 2009-01-21
Publication date: 2009-09-11
Anticipated expiration: 2010-07-21

Abstract

A process for the preparation of ethers of dihydroartemisinin containing more than 99 % of ß isomer from dihydroartemisinin which comprises: reacting dihydroartemisinin with an alcohol and hydrolysable organic halides as a pro-acid catalyst in the presence of a co-solvent at 0 - 45 °C; diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine; cooling the reaction mass to 0 °C-5 °C and stirring to obtain the solid product; filtering the solid to obtain the ethers of dihydroartemisinin; recrystallizing the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99 % of ß isomer.

Description

A NOVEL PROCESS FOR THE PREPARATION OF ETHERS OF DIHYDROARTEMISININ

FIELD OF INVENTION

The present invention relates to a novel process for the preparation of ethers of dihydroartemisinin, commonly known as artemether, the methyl ether derivative and arteether, the ethyl ether derivative. The present invention more particularly relates to a novel process for the preparation of artemether and arteether containing more than 99% of β isomer.

BACKGROUND OF THE INVENTION Millions of people in the world suffer from malaria. Malaria is widely spread disease in Africa and Asia. Each year, millions of children die due to this disease. Rapidly growing multi-drug resistant strains of malaria parasites made the therapy of this disease more difficult. Quinoline based drugs are becoming less effective against these resistant strains.

Artemisinin is a new class of compounds found to be effective in the treatment of uncomplicated/severe complicated/cerebral malaria. This class of compounds is found to be effective against multi-drug resistant strains. Artemisinin is derived from Artimisia annua. Derivatives of artemisinin are used either singly or in combination with other antimalarial drugs in the treatment of severe malaria and are effective against both chloroquine-resistant and sensitive strains of Plasmodium falciparum. Artesunate, arteether, artemether and dihydroartemisinin are among the preferred derivatives. Above mentioned compounds are safe, and do not have side effects.

Dihydroartemisinin is obtained from artemisinin by sodium borohydride reduction. Arteether, artemether and other ethers of dihydroartemisinin are generally prepared from dihydroartemisinin. Both α- and β- isomers of the ethers are formed during the synthesis. Arteether is sold as a mixture of α/β which is known as Rapither AB and as β-arteether known as Artemotil. Artemotil is injectable formulation of β-arteether in sesame oil and Betamotil is injectable formulation of β-arteether in Arachide oil. In 2006, β-arteether formulation, Artemotil was pre-qualified by WHO for the treatment of malaria. Artemether is sold as β-artemether.

It has been reported that α-arteether alone is slightly less active than β-arteether or mixture of α/ β-arteether. (Tripathi R, et.al., Am. J. Trop. Med. Hyg. 1991, 44: 560-563). The consistent finding that α-arteether has lower activity than the β-arteether is also reported in another prior art reference(Moshe J. Shmuklarsky, et.al., Am. J. Trop. Med. Hyg. 1993, 48(3), 377-

384). Plasmodium falciparum in vitro test data published in this report suggest that α- isomer of arteether may be less potent than its β- isomer. The test data also reveals that β-arteether is five fold more potent than mefloquine and approximately 90 fold more potent than chloroquine. The above reference also refers the Chinese studies that indicate β-isomer of artemether is more active than α-isomer of artemether.

The above mentioned studies clearly indicate that β-isomer is more active and hence more desirable.

Ethers of dihydroartemisinin are prepared from dihydroartemisinin by reacting it with an alkylating agent in the presence of a strong acid as catalyst in a suitable solvent.

Brossi et al. in J. MedChem. 1988, 31, 645-650 reported the preparation of arteether from dihydroartemisinin using boron trifluoride etherate in benzene-ethanol at 45°C. The product contained a mixture of α and β isomers along with other impurities.

Bhakuni et al. in Indian J. Chem. 1995, 34(B), 529-30 reported the preparation of arteether from dihydroartemisinin in alcohol and benzene mixture using chlorotrimethylsilane as acid catalyst. Pure arteether was obtained from the product mixture by column chromatography.

In J. Med. Chem., 1995, 38, 764-770, Lin et al. reported 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 191588 discloses a one pot process for the preparation of artemether wherein artemisinin is reduced to dihydroartemisinin by sodium borohydride which is converted to ether in the presence of a cation exchange resin wherein the ratio of dihydroartemisinin to the cation exchange resin is l:3.The product is obtained as mixture of α/β artemether which is separated by column chromatography to obtain pure α- and β- isomers.

US2004106809, WO2004050662 described a single pot conversion of artemisinin to arteether wherein use of chlorotrimethylsilane to get artether is also reported

IN 173947 discloses a process for the preparation of arteether wherein etherification of dihydroartemisinin is carried out using ethanol in dry benzene with boron trifluoride etherate as catalyst which produces a 70:30 diastereoisomeric mixture of arteether which is then fractionally crystallized to provide both the enantiomers.

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. The US patent corresponding to this process is US6346631.

Indian patent application 00542/DEL/2003 describes a process for the preparation of arteether by reacting dihydroartemisinin with dry. EtOH in toluene at 50-60° for 15 min. using anhydrous AICI₃ as catalyst. The product is obtained as a mixture of α- and β- isomers in the ratio of 29.6:71.8. Indian patent application 00432/MUM/2007 describes a process for the preparation of artemether by reacting dihydroartemisinin with MeOH in toluene using Me₃SiCl to give a mixture of α- and β -artemether.

A Chinese patent CNl 106012 describes a process which uses strong acids such as trifluoromethanesulfonic acid, perchloric acid in a mixture of aprotic solvent and alcohol.

Indian patent application 00013/DEL2007 describes a process for the preparation of artemether by reacting dihydroartemisinin with trimethylorthoforrnate in presence of p- toluenesulfonic acid as acid catalyst.

A recent publication by Novartis, OPRD (Organic process research and development) (2007), 11(3), 336-340, describes use of hydrochloric acid as acid catalyst.

The processes mentioned in the prior art suffer from draw-backs. The product ethers of dihydroartemisinin are obtained as oily mixture of α- and β- isomers which require separation by column chromatography. None of the prior art processes give process for direct isolation of β- isomer of the ethyl ether. The prior art processes also use high concentration of strong acids as catalysts making the processes uneconomical.

Hence there is a need to develop a simple and economical process which will give β- isomer of ethers of dihydroartemisinin in high purity and yield.

Inventors of the present invention have surprisingly found out that β- isomer of ethers of dihydroartemisinin can be obtained in a high yield and purity by reacting dihydroartemisinin with an alcohol and acid chloride as a pro-acid catalyst in the presence of a co-solvent such as trialkylorthoformate. The amount of pro-acid catalyst required to carry out reaction of the present invention is very small as compared to the catalysts used in the prior art. 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 containing more than 99% of β- isomer.

It is another object of the present invention to provide a process for the preparation of artemether and arteether containing more than 99% of β- isomer in high yield with a simple isolation procedure.

It is yet another object of the present invention to provide a process for the preparation of artemether and arteether by using a pro-acid catalyst in very small amount.

It is another object of the present invention to provide a cost effective and an environmentally friendly process for the preparation of ethers of dihydroartemisinin as the amount of catalyst required is very small.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided a novel process for the preparation of ethers of dihydroartemisinin containing more than 99% of β isomer from dihydroartemisinin comprising the steps of: a) Reacting dihydroartemisinin with an alcohol in presence of a pro-acid catalyst and in the presence of a co-solvent at 0 - 45°C. b) Diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine c) Cooling the reaction mass to 0°C-5°C and stirring to obtain the solid product d) Filtering the solid to obtain the ethers of dihydroartemisinin e) Recrystallising the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99% of β isomer. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for the preparation of ethers of dihydroartemisinin, more particularly artemether and arteether

The present invention particularly relates to a novel process for the preparation of artemether or arteether containing more than 99% of β isomer from dihydroartemisinin which comprises: a) reacting dihydroartemisinin with an \ alcohol and hydrolysable organic halides as a pro-acid catalyst in the presence of a co-solvent at 0 - 45°C b) diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine c) cooling the reaction mass to 0°C-5°C and stirring to obtain the solid product d) filtering the solid to obtain the ethers of dihydroartemisinin e) recrystallizing the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99% of β isomer

According to another aspect of the invention, the product (β- isomer) obtained after a simple work up is a crystalline solid with >99% purity.

In a process of the present invention dihydroartemisinin is reacted with an alcohol and acid halide as a pro-acid catalyst in the presence of a co-solvent to obtain artemether or arteether containing more than 99% of β isomer.

In an embodiment of the present invention the pro-acid catalyst is selected from aliphatic acid halide, aromatic acid halide, and inorganic acid halide or sulfonyl chloride.

Preferably, aliphatic acid halide is selected form acetyl chloride, acetyl bromide, pivaloyl chloride, oxalyl chloride, more preferably acetyl chloride. Preferably aromatic acid halide is selected form benzoyl chloride or reactive halo compounds such as benzotrichloride

Preferably inorganic acid chloride is selected from sulfur or phosphorus oxy chloride and trimethyl silylchloride, more preferably thionyl chloride.

Preferably sulfonyl chloride is selected from methane sulfonylchloride, bezene sulfonylchloride or p-toluene sulfonyl chloride.

In another embodiment of the present invention the ratio of dihydroartemisinin to pro-acid catalyst is from 1:0.01 to 0.1 preferably 1: 0.02 to 0.05, more preferably 1: 0.03.

In another embodiment of the present invention the co-solvent is selected from trialkylorthoformate, tiralkylorthoaceate, liquids having acetal or ketal functional groups such as 2,2-dimethoxypropane, or enol ethers such as 2-methoxypropene, preferably trialkyl orthoformates.

In yet another embodiment of the present invention the ratio of dihydroartemisinin to the co- solvent is 1: 0.1 to 1:6 preferably 1: 2 to 1:4.

In yet another embodiment of the present invention the ratio of dihydroartemisinin to the alcohol is 1:3 to 1:12, preferably 1:6.

In yet another embodiment of the present invention the reaction is carried out between O⁰C- 45⁰C, preferably between 5°C-30°C, more preferably between 10⁰C-15°C.

Another aspect of the present invention is to provide a process for the preparation of artemether and arteether by using an acid chloride as a pro-acid catalyst in very small amount (mole percent 0.03 to 0.06 with respect to dihydroartemisinine). Inventors of the present invention found out that the desired product is obtained using very less quantity of pro-acid catalyst as compared to the other acid catalysts that are used in the prior art. It makes the process of the present invention cost effective and environmentally friendly.

It has been observed that low concentration of dry acid in the reaction is achieved by the use of low concentration of acid chloride pro-catalyst. Thus, the low concentration of acid chloride catalyst avoids the formation of by-product and yields the desirable β -isomer in high yield and purity.

In prior art, typically the ratio of dihydroartemisinin to the acid catalyst is very high as evident from the following examples.

US 6346631 discloses the use of dihydroartemisinin and solid acid catalyst in the ratio of 1 to 2:1.

IN191588 describes the use of dihydroartemisinin and cation exchange resin in the ratio of 1:3.

Whereas, the ratio of dihydroartemisinin to pro-acid catalyst used in the present invention is 1:0.03 to 1:0.06

In yet another aspect of the present invention the product is isolated by easy work up procedure wherein the reaction mass after treating with a mild aqueous base cooled to O⁰C- 5°C and the precipitated product is filtered which is then recrystallised from a mixture of alcohol and water to get the ethers of dihydroartemisinin containing more than 99% pure β- isomer. 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.

Dihydroartemisinin used in the examples was prepared by methods known in the literature.

The final products were analyzed as per specification given in the International Pharmacopoeia, 4^th edition.

The beta isomer was confirmed by NMR and showed characteristic proton signal for ClO-H.

EXAMPLES

Example 1: Synthesis of artemether

Dihydroartemisinin (25 g, 0.088 mole), methanol (75 ml) and trimethyl ortho formate (50 ml

/48.5 g =0.457 mole) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10-15°C and acetyl chloride (0.24 ml / 0.265 g = 0.0034 mole) was added. Stirring was continued at 10-15°C for another 3hs or till the end of the reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution (0.25g in 150 ml water). The reaction mass was then cooled to 0°C-5°C and stirred for 2 hours. The precipitated product was filtered and washed with methanol: water (1:1, 2 X 25 ml). The product was suck-dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid. Yield: 19.6g, (74.67%); m.p.: 86°C-90°C; W_D ²⁰: +166° to +173° (1% solution in dehydrated methanol). HPLC purity > 99%

¹HNMR : δ 0.94 (doublet, 3H), δ 0.96 (doublet, 3H), δ 1.28 (multiplet, 2H), δ 1.45 (singlet, 3H), δ 1.46-1.47 (multiplet, 2H), δ 1.60-1.61 (multiplet, IH), δ 1.65-1.66 (multiplet, IH), δ 1.74-1.77 (multiplet, 2H), δ 1.86-1.90 (multiplet, IH), δ 2.00-2.01 (multiplet, IH), δ 2.05- - 2.07 (multiple!, IH), δ 2.34-2.43 (multiple!, IH), δ 2.62-2.64 (multiplet, IH), δ 3.43 (singlet, 3H), δ 4.69-4.70 (doublet, IH), δ 5.39 (singlet, IH)

Example 2: Synthesis of arteether Dihydroartemisinin (25 g, 0.088 mole), ethanol (75 ml) and triethyl ortho formate (50 ml / 44.55 g = 0.301 mole) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10-15°C and acetyl chloride (0.24 ml / 0.265 g =0.0034 mole) was added. Stirring was continued at 10-15°C for another 3hs or till the end of the reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution (0.25g in 150 ml water). The reaction mass was then cooled to 0°C-5°C and stirred for 2 hours. The precipitated product was filtered and washed with ethanol: water (1 :1, 2 X 25 ml). The product was suck-dried and then recrystallised from ethanol: water (1:1) to get the title product as white crystalline solid. Yield: 19.6g, (71.38%); m.p.: 81°C-84°C; [α]_D ²⁰: +155° to +157° (2% solution in dehydrated ethanol). HPLC purity > 99%

¹HNMR : δ 0.91 (doublet, 3H), δ 0.96 (doublet, 3H), δ 1.16-1.18 (triplet, 3H), δ 1.21-1.34 (multiplet, 3H), δ 1.44 (singlet, 3H), δ 1.47-1.62 (multiplet, 2H), δ 1.65-1.66 (multiplet, IH), δ 1.7-1.91 (multiplet, 3H), δ 2.01-2.06 (multiplet, IH), δ 2.32-2.38 (multiplet, IH), δ 2.62-2.64 (multiplet, IH), δ 3.43 & 3.86 (multiplet, 2H), δ 4.80 (doublet, IH), δ 5.41 (singlet, IH)

EXAMPLE 3 Dihydroartemisinin (10g,0.0352 mole), methanol (60ml) and trimethylorthoformate (40ml , 38.8 g, 0.366 mole) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 20 - 25 ⁰C and p-toluene sulfonyl chloride (0.15 g, 0.0008 mole) was added. Stirring was continued at 20 - 25 ⁰C for 4 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then cooled to 20 - 25 ⁰C and stirred for 2 hours. The precipitated product was filtered and washed with methanol: water (1:1). The product was suck dried and then recrystallised from methanol:water (1 : 1) to get the title product as white crystalline solid. Yield 6. I g. HPLC purity >99%

EXAMPLE 4

Dihydroartemisinin (1Og), methanol (60ml) and trimethylorthoformate (40ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and methane sulfonyl chloride (0.15 ml) was added. Stirring was continued at 10 - 15 ⁰C for 12 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then cooled to 0 - 5 ⁰C and stirred for 2 hours. The precipitated product was filtered and washed with methanohwater (1:1). The product was suck dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid. Yield 3.9 g. HPLC purity >99%

EXAMPLE 5 Dihydroartemisinin (1Og), methanol (60ml) and trimethylorthoformate (40ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and acetyl bromide (0.15 ml) was added. Stirring was continued at 10 - 15 ⁰C for 3 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then cooled to 0 - 5 ⁰C and stirred for 2 hours. The precipitated product was filtered and washed with methanol : water (1:1). The product was suck dried and then recrystallised from methanol:water (1 :1) to get the title product as white crystalline solid. Yield 6.6 g. HPLC purity >99% EXAMPLE 6

Dihydroartemisinin (1Og), methanol (30ml) and trimethylorthoformate (20ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and thionyl chloride (0.1 ml) was added. Stirring was then continued at ambient temperature for 8 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanol:water (1:1). The product was suck dried and then recrystallised from methanol:water (1:1) to get the title product as white crystalline solid.

Yield 6.5 g. HPLC purity >99%

EXAMPLE 7 Dihydroartemisinin (1Og), methanol (60ml) and 2-methoxypropene (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and methane sulfonyl chloride (0.15 ml) was added. Stirring was continued at 10 - 15 ⁰C for 10 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then cooled to 0 — 5 ⁰C and stirred for 2 hours. The precipitated product was filtered and washed with methanol: water (1:1). The product was suck dried and then recrystallised from methanol:water (1:1) to get the title product as white crystalline solid. Yield 6.2 g. HPLC purity >99%

EXAMPLE 8

Dihydroartemisinin (5g), methanol (30ml) and 2-methoxypropene (20ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and methane sulfonyl chloride (0.1 ml) was added. Stirring was continued at ambient temperature for 3 hours or-till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanol.water (1 : 1). Yield 3.5 g. HPLC purity >99%

EXAMPLE 9

Dihydroartemisinin (1Og), methanol (30ml) and 2-methoxypropene (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and thionyl chloride (0.1 ml) was added. Stirring was continued at ambient temperature for 10 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanol: water (1:1). The product was suck dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid.

Yield 6 g.

HPLC purity >99%

EXAMPLE 10 Dihydroartemisinin (1Og), methanol (60ml) and 2,2-dimethoxypropane (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and trimethylsilyl chloride (0.15 ml) was added. Stirring was continued at 10 - 15 ⁰C for 9 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then cooled to 0 - 5 ⁰C and stirred for 2 hours. The precipitated product was filtered and washed with methanohwater (1:1). The product was suck dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid. Yield 4.7 g. HPLC purity >99% EXAMPLE 11

Dihydroartemisinin (5g), methanol (30ml) and 2, 2-dimethoxypropane (20ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and trimethylsilyl chloride (0.1 ml) was added. Stirring was continued at ambient temperature for 3 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanokwater (1:1). Yield 3 g HPLC purity >99%

EXAMPLE 12

Dihydroartemisinin (1Og), methanol (60ml) and 2, 2-dimethoxypropane (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and methane sulfonyl chloride (0.15 ml) was added. Stirring was continued at ambient temperature for 9 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanol: water (1 :1). The product was suck dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid. Yield 5.2 g. HPLC purity >99%

EXAMPLE 13 Dihydroartemisinin (1Og), methanol (60ml) and 2, 2-dimethoxypropane (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and benzotrichloride (0.15 ml) was added. Stirring was continued at ambient temperature for 9 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and- washed with methanol:water (1:1). The product was suck dried and then recrystallised from methanol:water (1:1) to get the title product as white crystalline solid. Yield 5 g. HPLC purity >99%

EXAMPLE 14

Dihydroartemisinin (1Og), methanol (60ml) and 2,2-dimethoxypropane (2ml) were stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 10 - 15 ⁰C and methane sulfonyl chloride (0.15 ml) was added. Stirring was continued at ambient temperature for 9 hours or till the end of reaction (monitoring by TLC). The reaction mixture was diluted with sodium bicarbonate solution. The reaction mass was then stirred for 2 hours. The precipitated product was filtered and washed with methanokwater (1:1). The product was suck dried and then recrystallised from methanol: water (1:1) to get the title product as white crystalline solid. Yield 5.2 g. HPLC purity >99%

Claims

1. A process for the preparation of ethers of dihydroartemisinin containing more than

99% of β isomer from dihydroartemisinin which comprises: a) reacting dihydroartemisinin with an alcohol and hydrolysable organic halides as a pro-acid catalyst in the presence of a co-solvent at 0 - 45⁰C; b) diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine; c) cooling the reaction mass to 0°C-5°C and stirring to obtain the solid product; d) filtering the solid to obtain the ethers of dihydroartemisinin; e) recrystallizing the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99% of β isomer.

2. The process as claimed in claim 1 wherein the ether of dihydroartemisinin is selected artemether and arteether.

3. The process as claimed in claim 1 wherein pro-acid catalyst is selected from aliphatic acid halide, aromatic acid halide, and inorganic acid halide or sulfonyl chloride.

4. The process as claimed in claim 1 wherein the pro-acid catalyst used is in amount of mole percent 0.03 to 0.06 with respect to dihydroartemisinine.

5. The process as claimed in claim 3 wherein the aliphatic acid halide is selected form acetyl chloride, acetyl bromide, pivaloyl chloride, oxalyl chloride, more preferably acetyl chloride.

6. The process as claimed in claim 3 wherein the aromatic acid halide is selected form benzoyl chloride or reactive halo compounds such as benzotrichloride.

7. The process as claimed in claim 3 wherein the inorganic acid chloride is selected from sulfur or phosphorus oxy chloride, trimethylsilyl chloride ,more preferably thionyl chloride.

8. The process as claimed in claim 7 wherein the sulfonyl chloride is selected from methane sulfonylchloride, bezene sulfonylchloride or p-toluene sulfonyl chloride.

9. The process as claimed in claim 1 wherein the ratio of dihydroartemisinin to pro-acid catalyst is from 1 :0.01 to 0.1 preferably 1 : 0.02 to 0.05, more preferably 1 : 0.03.

10. The process as claimed in claim 1 wherein the co-solvent is selected from trialkylorthoformate, tiralkylorthoaceate, liquids having acetal or ketal functional groups or enol ethers.

11. The process as claimed in claim 1 wherein the ratio of dihydroartemisinin to the co- solvent is 1: 0.1 to 1:6 preferably 1: 2 to 1:4.

12. The process as claimed in claim 1 wherein the ratio of dihydroartemisinin to the alcohol is 1:3 to 1:12, preferably 1 :6

13. The process as claimed in claim 1 wherein the reaction is carried out between O⁰C- 45⁰C, preferably between 5°C-30°C, more preferably between 10°C-15°C.