FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -"AN IMPROVED PROCESS FOR THE PREPARATION OF ETHERS OF DIHYDROARTEMISININ"
2. Applicant(s)
(a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: A-37/38, MIDC Phase-I, Golavli, Kalyan-Shil Road, Dombivli (East)
Dist-Thane 421 203.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF INVENTION
The present invention relates to an improved 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 an improved process for preparation of artemether and arteether containing more than 99% of (3 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 a- and P- isomers of the


ethers are formed during the synthesis. Arteether is sold as a mixture of a/p which is known as Rapither AB and as P-arteether known as Artemotil. Artemotil is injectable formulation of P-arteether in sesame oil and Betamotil is injectable formulation of P-arteether in Arachide oil. In 2006, P-arteether formulation, Artemotil was pre-qualified by WHO for the treatment of malaria. Artemether is sold as p-artemether.
It has been reported that a-arteether alone is slightly less active than P-arteether or mixture of a/ P-arteether. (Tripathi R, et.al., Am. J. Trop. Med. Hyg. 1991, 44: 560-563). The consistent finding that a-arteether has lower activity than the p-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 a- isomer of arteether may be less potent than its P-isomer. The test data also reveals that P-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 P-isomer of artemether is more active than a-isomer of artemether.
The above mentioned studies clearly indicate that P-isomer is more active and hence more desirable.
Brossi et al. J. Med.Chem. 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 a and P isomers along with other impurities.
Bhakuni et al. 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.
IN191588 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. The product is obtained as mixture of a/p artemether which is separated by column chromatography to obtain pure a- and P-isomers.
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 a- and P- isomers in the ratio of 30:70.
The processes mentioned in the prior art suffer from draw-backs. The product ethers of dihydroartemisinin are obtained as oily mixture of a- and P- isomers which require separation by column chromatography. None of the prior art processes give process for direct isolation of pure P- isomer of the ethyl ether.


Hence there is a need to develop a simple and economical process which will give P- isomer of ethers of dihydroartemisinin in high purity and yield.
Inventors of the present invention have surprisingly found out that p-isomer of ethers of dihydroartemisinin can be obtained in a high yield and purity by reacting dihydroartemisinin with trialkyl formate in an alcoholic solvent in the presence of a dry cation exchange resin with a moisture content <3 % (hereinafter called as resin). According to another aspect of the invention, the product (P- isomer) obtained after a simple work up is a crystalline solid with >99% purity.
OBJECT OF THE INVENTION
It is an object of the present invention to provide an improved process for the preparation of ethers of dihydroartemisinin, more particularly artemether and arteether containing more than 99% of p- isomer.
It is another object of the present invention to provide a process for the preparation of pure P-isomer (>99%) of artemether and arteether directly without any purification step.
It is another object of the present invention to provide a process for the preparation of artemether and arteether containing more than 99% of P-isomer in higher yield with 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 dry cation exchange resin as a catalyst in lesser amount.


It is a further object of the present invention to reduce the quantity of starting material such as trialkylformate due to the use of dry cation exchange resin.
It is another object of the present invention to provide cost effective and simple process for the preparation of ethers of dihydroartemisinin.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved process for the preparation of ethers of dihydroartemisinin containing more than 99% of p isomer from dihydroartemisinin comprising the steps of:
a) Reacting dihydroartemisinin with trialkylformate in the
presence of a dry resin with a moisture content < 3% in an
alcoholic solvent at 0°C-25°C;
b) Filtering the reaction mixture and removing resin after the
reaction is complete;
c) Concentrating the filtrate in vacuum at less than 40°C;
d) Diluting the filtrate with water;
e) Cooling the filtrate to 0°C-5°C and stirring to get the solid product;
f) Filtering the solid to obtain the ethers of dihydroartemisinin containing more than 99% of p isomer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of ethers of dihydroartemisinin, more particularly artemether and arteether


The present invention particularly relates to an improved process for preparation of artemether and arteether containing more than 99% of p isomer from dihydroartemisinin which comprises:
a) Reacting dihydroartemisinin with trialkylformate in the presence of a dry resin with a moisture content < 3% in an alcoholic solvent at 0°C-25°C;
b) Filtering the reaction mixture and removing resin after the reaction is complete;
c) Concentrating the filtrate in vacuum at less than 40°C ;
d) Diluting the filtrate with water;
e) Cooling the filtrate to 0°C-5°C and stirring to get the solid product;
f) Filtering the solid to obtain the ethers of dihydroartemisinin containing more than 99% of P isomer.
The present inventors found that the amount of resin required for the reaction is lesser due to the use of the resin with a moisture content < 3%. Use of the resin for the present invention also reduces the quantity of trialkylformate used in the reaction. It has been also found that dry resin remarkably affects the a: P isomer ratio. Thus, dry resin plays a vital role in the present invention.
In a process of the present invention dihydroartemisinin is reacted with trialkylformate in the presence of a dry resin and alcoholic solvent at 0°C-25°C to obtain artemether and arteether containing >99% of P isomer.
In an embodiment of the present invention the ratio of dihydroartemisinin to trialkylformate is from 1:2 to 1:10, preferably 1:2 to 1:4, more preferably 1:2.5 to 1: 3.5


In an another embodiment of the present invention trialkylformate is selected from triethyl formate and trimethyl formate
In yet another embodiment of the present invention dihydroartemisinin and dry cation exchange resin used are in the ratio of 10:1 to 1:1, preferably 5:1
In yet another embodiment of the present invention alcoholic solvent is selected from alcohol or mixture of alcohol and acetone, preferably methanol and mixture of ethanol and acetone (95:5). In yet another embodiment of the present invention the ratio of dihydroartemisinin to the alcoholic solvent is from 1:3 to 1:10, more preferably from 1:4 to 1:8, most preferably from 1:5 to 1:7.
In yet another embodiment of the present invention the reaction is carried out between 0°C-30°C, more preferably between 10°C-30°C, most preferably between 20°C-25°C
In another aspect of the present invention the product is isolated by easy work up procedure wherein the product is filtered and resin is collected after the reaction is complete, the filtrate is concentrated under vacuum, and then diluted with water. Cooling and stirring the filtrate at 0°C-5°C precipitates the product. The product is then filtered and dried to get the ethers of dihydroartemisinin which contains >99% pure P-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 dry resin may be commercial or pretreated in the lab to get the moisture content less than 3%. Further the resin may be recycled and utilized for subsequent batches.
The final products were analyzed as per specification given in the International Pharmacopoeia, 4th edition.
The beta isomer was confirmed by NMR and showed characteristic proton signal for C10-H.
EXAMPLES
Example 1: Synthesis of arteether
Dihydroartemisinin (100 g, 0.352 mole), commercial ethanol (ethanol: acetone = 95:5, 600 ml) and triethyl ortho formate (400 ml, 2.41 mole) were stirred at ambient temperature for 15 minutes. Dry cationic exchange resin (20g) was added and stirring continued for another 150 minutes or till the end of the reaction (monitoring by TLC). The catalyst was filtered off and washed with ethanol (20 ml). The filtrate was neutralized with sodium acetate (400 mg). Ethanol (100ml) was distilled at 25°C-30°C under vacuum from the above neutralized solution. Water (600 ml) was added and stirring continued at 25°C-30°C for 30 minutes. The solution 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 100 ml). The product was suck-dried and then air-dried to get the title product as white crystalline solid. Yield: 80g, (72.8%); m.p.: 81°C-84°C; [a]D20: +155° to +157° (2% solution in dehydrated ethanol).
Example 2: Synthesis of artemether
Dihydroartemisinin (100 g, 0.352 mole), methanol (600 ml) and trimethyl
ortho formate (400 ml, 3.66 mole) were stirred at ambient temperature for


15 minutes. Dry cationic exchange resin (20g) was added and stirring continued for another 150 minutes or till the end of the reaction (monitoring by TLC). The catalyst was filtered off and washed with methanol (20 ml). The filtrate was neutralized with sodium acetate (400 mg). Methanol (100ml) was distilled at 25°C-30°C under vacuum from the above neutralized solution. Water (600 ml) was added and stirring continued at 25°C-30°C for 30 minutes. The solution 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 100 ml). The product was suck-dried and then air-dried to get the title product as white crystalline solid. Yield: 80g, (76.19%); m.p.: 86°C-90°C; [a]D20 +166° to +173° (1% solution in dehydrated methanol).