IMPROVED PROCESS FOR THE PREPARATION OF ARTEETHER (p-ISOMER)
FIELD OF INVENTION
The present invention relates to a improved process for the preparation of arteether (P-[somer) formula I from dihydroartemisinin and useful for the treatment of malaria.


H,C

OCHjCHa
BACKGROUND OF THE INVENTION
A.Brossi, et.al, (Journal of medicinal chemistry, 1988, 31, 3,645-650), discloses a process for the preparation of arteether from artemesinin.This process yields a mixture of a: P isomers of areether in the ratio of 1:3.The acid catalyst used for the conversion of dihyroartemisinin to areether is BF3 - etherate in benzene. The ratio of benzene and ethanol used for the conversion is 11ml: 4 ml.
An Indian patent IN 173947 (1990) discloses an improved process for the preparation of a mixture a and P arteether in the ratio of 1:3 using BF3 etherate as an acid catalyst in benzene under reflux wherein they used benzene and ethanol in the ratio of 7.5: 3.5
Another Indian patent IN 180500 (1998) discloses an improved process for the preparation of a mixture of a: p arteether in the ratio of 1:3 using chlorotrimethyisilane as an acid catalyst in benzene ai room temperature.

Since benzene is carcinogenic, all the above methods are not industrially viable,
US patent 6346631 (2002), describes the process for the preparation of arteether using p-toluene sulphonic acid as an acid catalyst in presence of trialkylorthoformale at 40°C. This method also yields isomeric mixture of arteether.
Another US patent 2004/0106809, discloses a process for the preparation of arteether from artemesinin in a single step using trimethyl silyl chloride or p-Toleuncsulphonic acid and polyhydroxy catalyst such as dextrose,galactose function of which is not clear.
Therefore it is object of the present invention to provide a novel process for the preparation of isomericaily pure (3-isomer of arteether.
Another object of the present invention to provide a industrially viable and economically suitable process for the preparation of pure p- arteether.
Yet another object of the present invention is to provide a selective process to produce p-arteether which is about 90%.
Summary of invention
Accordingly, the present invention a novel process for the preparation of p-arteether comprising; converting artemesinin to dihydroartemesinin using sodium borohydride in methanol between -5'^C to lO^C; acetalization of dihydroartemesimn using ethanol and Iriethyiortho formate at the temperature between 15 to 40°C; treating dihydroartemesinin with acid catalyst such as tartaric acid, acetic acid, citric acid, oxalic acid to produce arteeether; isolating pure p- isomer of arteether by recrystallisation using hexane, heptane, cyclohexane, pet ether.

Another aspect of the present invention, the process provides a selective synthesis of (3-arteether in which formation of a-arteether is minimized and the proportion of the said p-arteether with respect to the a-arteether is 9 ■. 1.
Yet another aspect of the present invention, a novel process for the production of 99.9% isomerically pure p-arteether,
DETAILED DESCRIPTION OF PRESENT INVENTION:
As used herein the term 'organic acids' refers to tartaric acid, acetic acid, citric acid, oxalic acid and the like.
As used herein the term 'organic solvents' refers to alcohol, hexane, heptane, cyclohexane, pet ether and the like.
As used herein the term 'alcohor refers to methanol, elhanol, propanol, isopropanol and the like.
The present invention provides improved process for the preparation of arieether under reaction conditions that improve reaction yields and facilitate the process. In particular, the present invention is directed to the synthesis of p-arteether wherein the said process faciUtates 90% formation P-arteether and the proportion of the said P-arteether with respect to the a-arteether is 9:1 in the final product.
Using organic acids as a catalyst to convert dihydroartemesinin into arteelher it is beheved that the process of the present invention is more efficient than those disclosed in prior art. It is further proved that the processes of the present invention produce arteether in high yields, for example about 85 to about 95%. Furthermore, formation of p-arteether in the reaction mixture during conversion with respect to the u-arteether is 9:1, which is about 90%.

According to the present invention a novel process for the preparation of (3- arteether comprising;
a) converting artemesinin to dihydroanemesinin using sodium borohydride in methanol between -5T to 10°C;
b) acelylating dihydroartemesinin using ethanol and triethylortho formate at the temperature between 15 to 40°C;
c) treating and converting dihydroartemesinin with acid catalyst such as tartaric acid, acetic acid, citric acid, oxalic acid to produce arteeether;
d) isolating pure p- isomer of arteether by recrystallisation using hexane, heptane, cyclohexane, pet ether.

OCH3CH3
p- Arteether
The reaction temperature of conversion of artemesinin to dihydro artemesinin in step (a) is between -5°C to IQ°C preferably between 0°C to 5°C and most preferably between 0°C to -5°C.
The solvent used in the said step (a) is organic solvents, alkanol , hexane, heptane, cyclohexane, pet ether and the like. Preferably alkanol such as methanol, ethanol.

propanol, isopropanol and the like, more preferably methanol and ethanol, most preferably methanol.
The acetalization of dihydroartemesinin in step (b) the reaction temperature is between 15 to 40°C preferably 20 to 30°C. The solvent used in step (b) is organic solvents, alkanol, hexane, heptane, cyclohexane, pet ether and the like. Preferably alkanol such as methanol, ethanol, propanol, isopropanol and the like, more preferably methanol and ethanol, most preferably ethanol.
Conversion of dihydroartemesinin to arteeether is performed in step (c) using an acid catalyst like tartaric acid, acetic acid, citric acid or oxalic acid, preferably tartaric acid or oxalic acid, more preferably oxalic acid.
In isolation step (d) pure p- isomer of arteether is obtained by recrystallisation using hexane, heptane, cyclohexane or pet ether, preferably, hexane and pet ether.

ARTEMESININ

DIHYDROARTEMESiNIN

H-,C

ARTEETHR(BETA ISOMER) Example 1 Preparation of dihydroartemesinin from artemesinin
To a solution of artemesinin (lOOg) in methanol (1.5 Lit) cooled to 0 to-5°C was added sodiumborohydride (20g) slowly during an hour and continued stirring for an hour at the same temperature. The solution was neutralized using acetic acid at 0 to-5°C. Methanol was distilled from the reaction under vacuum and ice cold water was added to the mixture with stirring. The product was filtered and the material was dried under vacuum.
Yield: 90-95 g. 95 %w/w
Example II

Preparation of arteether (a: p - Isomer)
To a mixture of ethanol (450 ml) and triethyl orthoformate (450 ml) containing oxalic acid (0.75 mole) at 20-25°C was added Dihydroartemesimn (90g) with stirring The reaction mixture was further stirred for 1 hr at the same temperature and neutralized with saturated sodium bicarbonate solution. The organic layer was washed with water and the solvent mixture distilled out under vacuum. The gummy residue material obtained was dried under high vacuum to yield a mixture of a: p arteether in the ratio of 1:9
Vield: 90 g.
Example III
Preparation of pure p -arteether
The isomeric mixture of arteether (90g) in pel ether (200ml) was cooled to -5° to -IO°Cand left over night. The crystallized material was filtered and dried under high vacuum to yield the pure ^-arteether (greater than 99% purity)
Yield; 65 g

We claim:
1. An improved process for the preparation of p arteether from artemesisnin which
comprising:
a. converting artemesinin to dihydroartemesinin using sodium borohydride
in an organic solvent at temperature between -S^C to 10°C;
b. treating dihydroartemesinin obtained in step (a) using an organic solvent
and triethylortho formate at the temperature between 15 to 40''C;
c. converting dihydroartemesinin with acid catalyst to produce arteeether;
d. isolating pure p- isomer of arteether by recrystallisation using an organic
solvent.
2. A process for preparation of p arteether as claimed in claim 1, wherein the reaction temperature of conversion of artemesinin into dihydroartemesinin in step (a) is between -5°C to 10°C preferably between 0°C to S^C and most preferably between 0°Cto-5°C,
3. A process for preparation of p arteether as claimed in claim !,wherein the solvent used in the said step (a) is organic solvents, alkanol, hexane, heptane, cyclohexane, pet ether and the like; preferably alkanol such as methanol, ethanol, propanol, isopropanol and the like, more preferably methanol and ethanol, most preferably methanol.
4. A process for preparation of P arteether as claimed in claim 1, wherein the acetalization of dihydroartemesinin in step (b) is effected at the temperature between 15 to 40°C C preferably 20 to 30°C and most preferably between 25° to 30°C.
5. A process for preparation of p arteether as claimed in claim 1, wherein the solvent used in step (b) is organic solvents such as alkanol , hexane, heptane.

cyclohexane, pet ether and the like; preferably alkanoi such as methanol, ethanol, propanol, isopropanol and the like, more preferably methanol and ethanol, most preferably ethanol.
6. A process for preparation of P arteether as claimed in claim 1, wherein conversion of dihydroartemesinin to arteeether is performed in step (c) using an acid catalyst such as tartaric acid, acetic acid, citric acid or oxalic acid and the like, preferably tartaric acid or oxalic acid, more preferably oxalic acid.
7. A process for preparation of [3 arteether as claimed in claim 1, wherein the product obtained in step (c) is an isomeric ratio of a: |3 areether 1:9.
8. A process for preparation of P- arteether as claimed in claim 1, wherein in step (d) the isolation of pure P- arteether is obtained by recrysiallisation using hexane, heptane, cyclohexane, pet ether, preferably hexane and pet ether as a solvent and most preferably pet ether.
9. A process for preparation of P- arteether as claimed in claim 1, wherein the said P" arteether is 99.9% pure compound.
10. A process for preparation of p- arteether is substantially herein described and
exemplified.

To
The Controller of Patents, Chennai.