FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2005
PROVISIONAL SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
PROCESS FOR THE PREPARATION OF ARTESUNATE FROM ARTEMISININ
2. APPLICANT (S)

NAME NATIONALITY ADDRESS

Almet Corporation Limited IN 332, Adhyaru Industrial Estate, Sun
Mill Compound, Lower Parel,
Mumbai-400 013, India

3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL SPECIFICATION
The following specification describes the invention.


FIELD OF INVENTION
The present disclosure relates to a process for preparation of artesunate, 10a-hemisuccinate of dihydroartemisinin, from artemisinin involving reduction of artemisinin to dihydro intermediate followed by its esterification. Artesunate and aretsunic acid are customary names of dihydroartemisinin hemisuccinate.
BACKGROUND OF THE INVENTION
Artemisinin and its ether and ester derivatives show antimalarial activity against multidrug resistant strains. Ether derivatives like arteether and artemether shows better activity but they suffer from some limitation like solubility, short half life. Unlike ether derivatives ester derivatives like artesunate has increased solubility and improved pharmacokinetic properties. The water insoluble artesunate is given orally in tablet form and water soluble artesunate sodium is given as I. V.
Artesunate was first prepared by Chinese scientists, using different methods. One of them describes acylation of dihydroartemisinin by succinic anhydride in pyridine at 30 °C for 24 hr with yield of 60 %. In another method, described in Acta. Chim. Sinica 40(6), 557-561., ester derivatives of dihydroartemisinin was prepared in presence of 4-(N, N-dimethylamino) pyridine and triethylamine as basic catalyst and 1,2 dichloroethane as solvent. The reaction is continued until complete conversion of dihydroartemisinin and product is isolated and purified by silica gel column giving overall yield 60 - 90 %.
Another improved method disclosed in US patent 654446, describes preparation of artesunate from dihydroartemisinin and succinic anhydride in presence of triethylamine as basic catalyst and in low boiling water miscible dry solvent like acetone. After completion of reaction, mixture is acidified and diluted with water to get artesunate. The yield of esterification is 96%.
U.S. patent 6677463 discloses one pot method for preparation of artesunate from artemisinin. Method describes reduction of artermisinin in to dihydroartemisinin in presence of polyhydroxy compound and sodium borohydride. After completion of reaction succinic anhydride and anion exchange resin was added to reaction mass and


stirred for 2 hrs. Then cold water was added and product was extracted with ethylacetate hexane mixture in Ph range of 6- 7. Distilling off the solvent yields the crude artesunate which on silica gel column purification gives 93 % of pure artemisinin.
DESCRIPTION OF THE INVENTION
The present disclosure relates to a two step process for synthesis of ester

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).
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, esterification of dihydroartemisinin is carried out in presence of basic catalyst and succinic anhydride as acylating agent, in a suitable solvent to give ester derivatives of artemisinin. Reaction is carried out at temperature ranging from 20-50 °C for 10 to 60 minutes, followed by washing with water at Ph 4 - 6, brine, drying organic layer over anhydrous sodium sulphate and concentrating organic layer to get crude hemisuccinate of dihydroartemisinin. Crude hemisuccinate of dihydroartemisinin is crystallized from hydro alcoholic mixture.
The basic catalyst used is either organocatalyst or inorganic bases. Organocatalyst used for esterification of dihydroartemisisin is imidazole or its imidazole derivatives like 4-methyl imidazole, 5-methyl imidazole most preferably imidazole. The ratio of artemisinin and organocatalyst is used in the range of 1:0.05 to 1:0.25 w/w.
Inorganic base used for esterification is form class of carbonate or bicarbonate base like ammonium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. The ratio of artemisinin to inorganic base is 1: 0.8 to 1: 1.5 mole equivalents.


Succinic anhydride is used as acylating agent for esterification of artemisinin to artesunate. The ration of artemisinin to succinic anhydride is 1:1 to 1:1.5 mole equivalents.
The suitable solvent is selected from the class of aprotic solvent, like chloroform, tetrahydrofuran, dichloromethane, dioxane, ether most preferably dichloromethane. The ratio of artemisinin to solvent is 1:5 to 1:8 w/v.
The esterification is carried out at a temperature range of 20 to 50 °C for 10 to 60 minutes, most preferably in range of 25 to 35 °C and for 15 to 40 minutes.
The yield obtained of the artesunate from artemisinin is in the range of 100 -110 %w/w.