FORM 2
THE PATENTS ACT 1970
(39 of 1970) &The Patent Rules 2005
PROVISIONAL SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTIONPROCESS FOR THE PREPARATION OF ETHER DERIVATIVES OF ARTEMISININ

2. APPLICANT (S)
NAME NATIONALITY ADDRESS
Almet Corporation Limited Indian 332, Adhyaru Industrial Estate, Sun Mill Compound, Lower Parel, Mumbai - 400 013
3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL SPECIFICATION The following Specification describes the invention


PROCESS FOR THE PREPARATION OF ETHER DERIVATIVES OF ARTEMISININ
FIELD OF INVENTION
The present disclosure relates to a process for preparation of ether derivatives of artemisinin involving reduction of artemisinin to dihydro intermediate followed by its etherification.
BACKGROUND OF THE INVENTION
Artemisinin and its derivative artemether, arteether, artelinate and artesunate are a class of antimalarials compounds derived from Artemisia annua which are now proving their promising activity and are being used for the treatment of uncomplicated severe complicated/cerebral and multi drug resistant malaria. Dihydroartemisinin is derived from artemisinin, a sesquiterpene endoperoxide isolated from the plant Artemisia annua.
Arteether, an ethyl ether derivative of dihydroartemisinin, a drug introduced in India for the first time by Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow, has undergone extensive preclinical, animal, toxicological studies as well as clinical studies on Indian subjects for drug regulatory purposes. World Health Organization (WHO) has also recommended arteether as life saving antimalarial drug. Arteether is more potential as compared to artemisinin and is an ideal antimalarial drug especially for treating multi drug resistant and complicated strains of Plasmodium falciparum. Arteether shows rapid schizoticial action with quicker clearance rate, short fever clearance time with no side effects and low recrudescence rate.
Brossi et al (J. Med. Chem., 1988, 31, 646-649) reported a two step process for the preparation of arteether describing, reduction of artemisinin to dihydroartemisinin with 79% yield using excess of sodium borohydride in methanol at 0 to -5°C in 3 hours. In the second step, the dihydroartemisinin was converted to arteether in benzene and ethanol mixture using BF3 etherate at 70°C in 1 hour. Column chromatographic purification of
2

crude arteether isolated form reaction mixture yielded alpha and beta arteether in quantitative yield.
Lin et al (J. Med. Chem., 1995, 38, 764-770) disclosed a method of using BF3 etherate for conversion of dihydroartemisinin to arteether in anhydrous ether at room temperature for 24 hours followed by silica gel chromatography to yield 40-90% pure arteether.
Bhakuni et al (Indian J. Chemistry, 1995, 34B, 529-530) described the preparation of arteether, artemether and other ether derivatives from dihydroartemisinin using chlorotrimethylsilane as catalyst and appropriate alcohol in benzene in 2-4 hours at room temperature.
US 6,346,631 disclosed conversion of dihydroartemisinin to arteether using trialkylorthoformate in alcohol at 40°C for 10 hours in quantitative yield.
Chandan Singh et al (Tetrahedron Letters, 2002, 43, 7235-7237) disclosed a single pot conversion of artemisinin to its ether derivatives. The process described reduction of artemisinin with sodium borohydride/Amberlyst-15 combination and its in situ conversion to the desired ether derivative by addition of appropriate alcohol at room temperature for 72 hours. Column chromatography of crude product yielded 55% pure arteether.
US 6,750,356 disclosed a single pot conversion of artemisinin to arteether. The reduction of artemisinin to dihydroartemisinin was carried out by sodium borohydride in presence of polyhydroxy catalyst followed by conversion to arteether in presence of acid catalyst in 4 hours. Column chromatography of crude arteether yielded 80% pure alpha beta arteether.
3

DESCRIPTION OF THE INVENTION
The present disclosure relates to a two step process for synthesis of ether derivatives of artemisinin.

In first step, reduction of artemisinin is accomplished by treating it with a modified reducing agent, prepared in situ, in a suitable solvent to give dihydroartemisinin. The reducing agent is modified by dissolving the reducing agent and monohydroxy or dihydroxy compound in a suitable solvent. The reduction is carried out at a temperature ranging from 0 to 30 °C for 5 to 30 minutes to get dihydroartemisinin.
The reducing agent which is modified is selected form a group consisting of lithium aluminium hydride, sodium borohydride and ethoxy aluminium hydride, most preferably sodium borohydride.
The monohydroxy compound used in preparation of modified reducing agent is selected from a group of methanol, ethanol, or mixture of methanol and ethanol, most preferably ethanol. The dihydroxy compound used in preparation of modified reducing agent is C2 to C5 diol like ethanediol, 1,2-propanediol, 1,2-butanediol, 1,3-propanediol and 1,4-butanediol, most preferably 1,2-propanediol.
The ratio of artemisinin and mono or dihydroxy compound is in the range of 1:0.2 to 1:1 w/w (1:0.75 to 1:4 molar equivalents). The ratio of artemisinin and sodium borohydride used is in the range of 1:0.1 to 1:0.5 w/w (1:0.75 to 1:4 molar equivalents).
4

The suitable solvent is selected from the class of aprotic solvent, like chloroform, tetrahydrofuran, dichloromethane, toluene, ether, ethyl acetate and hexane or mixture of aprotic solvent with C3 to C4 branched or straight chain alcohols like Isopropanol, n-Propanol, 2-butanol and 1-butanol most preferably isopropanol.
The reaction is carried out at a temperature range of 0 to 30 °C for 5 to 60 minutes, most preferably in range of 10 to 20 °C and for 10 to 30 minutes.
In second step, etherification of dihydroartemisinin is carried out in presence of acid catalyst and alcohol in a suitable solvent to give ether derivatives of artemisinin. Reaction is carried out at temperature ranging from 20-50 °C for 30 to 180 minutes, followed by washing with brine, drying organic layer over anhydrous sodium sulphate and concentrating organic layer to get ether derivative of artemisinin.
The etherification is carried out most preferably at temperature of 25-35° C for 40 to 120 minutes.
The acid catalyst used can be a liquid acid catalyst or a supported acid catalyst.
The liquid acid catalyst is BF3 etherate or a mineral or organic acid. The ratio of artemisinin and liquid acid catalyst is used in the range of 1:0.1 to 1:0.5 w/w.
In supported acid catalyst, the support is used from the group of silica gel, alumina, zeolites, and charcoal whereas the acids used are mineral acid, organic acid and Lewis acid. The mineral acid used is either sulfuric acid or hydrochloric acid and organic acid is selected from a group of formic, acetic, phosphoric and aryl sulfonic acid. The Lewis acid is selected from a group consisting of cobalt chloride, cupric chloride, indanium chloride, ferric chloride and zinc chloride. The ratio of acid catalyst and support used is in the range of 1:3 to 1:6 w/w. The ratio of artemisinin and supported acid catalyst is in the range of 1:0.3 to 1:1.5 w/w.
5

The yield obtained of the arteether from artemisinin is in the range of 85-90 %w/w. Dated 18th Day of January 2007

T.Srinivasan
Of Lakshmikumaran & Sridharan
Agent for the Applicant
To
The Controller of Patents,
Patent Office at Mumbai