Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-24
2002-02-12
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S450000
Reexamination Certificate
active
06346631
ABSTRACT:
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of arteether. Arteether is an ethyl ether derivative of dihydroartemisinin. The dihydroartemisinin is derived from artemisinin, which is a unique sesquiterpene lactone isolated from the plant
Artemisia annua
. Arteether prepared for the process of the invention is useful for the treatment of uncomplicated/severe complicated/cerebral and multi-drug resistant malaria.
BACKGROUND OF THE INVENTION
Approximately, 300-400 million people world wide now suffer from malaria, and each year 1-3 million (mostly children) die from this infectious disease. The rapidly spreading multi-drug resistance of parasite to standard quinoline based antimalarial drugs such as chloroquine and mefloquine complicates chemotherapy treatment of malarial patients. A new class of non-alkaloidal antimalarial compounds artemisinin (derived from
Artemisia annua
) and its semi-synthetic derivatives, artemether, arteether and artesunate as well as promising artelinic acid are increasingly being used for the treatment of uncomplicated/severe complicated/cerebral and multi-drug resistant malaria.
Arteether is a totally new drug introduced in India and has under gone extensive preclinical, animal, toxicological studies as well as clinical studies in Indian subjects as per drug regulatory requirements. Arteether is an ideal antimalarial drug especially for treating drug resistant and complicated
P. falciparum
malaria. Arteether show rapid schizontocidal action with quicker parasite clearance rate and short fever clearance time, virtually with no side effects and low recrudescence rate.
Brossi, et al (Brossi A; Vengopalan, B.; Dominguez Gerpe, L; Yeh, H. J. C.; Flipper-Anderson, J. L. Buchs, P; Luo, X. D.; Miehous, W and Peters, W. J. Med. Chem. 31, 646-649, 1988) report the isolation of arteether by dissolving dihydroartemisinin in a solvent mixture of benzene and ethanol by heating the solution at 45° C., followed by addition of BF
3
-etherate and reaction mixture was refluxed at 70° C. for 1 hr. The reaction mixture was washed with 10% sodium acetate solution and extracted by dichloromethane, dried over anhydrous sodium sulphate followed by evaporation yielded &agr;, &bgr; mixture of arteether and some side products. Chromatography of the reaction product was done to remove some impurities formed during the reaction.
EL-Feraly et al (F. EL-Feraly, M. A. Al-yahYa, K Y. Orabi, D. R. McPhail and A. T. McPhail J. Nat. Prod. 55, 878-883,1992) report the preparation of arteether by a process in which anhydrodihydroartemisinin, prepared from the artemisinin, was dissolved in absolute alcohol. The reaction mixture was stirred in presence of p-toluene sulphonic acid used as a catalyst. Upon workup, it yielded a mixture of &bgr; arteether and C-11 epimer in the ratio 3:1. In this process, only &bgr; arteether is obtained and separation of its C-11 epimer is difficult and preparation of anhydrodihydroartemisinin is a tedious process. The reaction took 22 hours to complete. The Lewis acid catalyst used in this reaction is required in large amount (60 mg acid catalyst by 100 mg anhydrodihydroartemisinin).
Another method is reported by Bhakuni et al. (Bhakuni R. S; Jain D. C and Sharma, R P., Indian J. Chemistry, 34B, 529-30 (1995). Arteether was prepared by dissolving dihydroartemisinin in alcohol and benzene mixture and then adding chlorotrimethylsilane as acid catalyst. The reaction was stirred for 2 hrs. at room temperature. The reaction mixture was washed with 10% sodium acetate solution and workup as usual method. The other products formed during the reaction were removed by column chromatography, to obtain pure arteether.
Another method is reported by Lin et al. (A. J Lin and R. E. Miller. J. Med. Chem. 38, 764-770 1995), in which the new ether derivatives were prepared by dissolving dihydroartemisinin in anhydrous ether and adding appropriate alcohol followed by boron trifluoride etherate. The reaction mixture was stirred at room temperature for 24 hrs. The yield of purified products ranged from 40-90%. Purification was achieved by the use of silica gel chromatography.
The above methods suffer from some disadvantages. Benzene is used as solvent, which on work up left a few non-volatile impurities in the reaction product. Also, the use of benzene as a solvent is not acceptable in Europe due to its carcinogenic nature. The minor products formed during the reaction require separation by column chromatography, thereby causing loss of arteether yield.
OBJECTIVES OF THE INVENTION
It is an object of the invention to provide an improved process for the preparation of arteether by replacing benzene as a solvent.
It is another object of the invention to obtain pure arteether without requiring chromatography to separate minor by-products.
It is a further object of the invention to replace the liquid acid catalyst used in the prior art by a solid acid catalyst.
It is a further object of the invention to provide a process the preparation of arteether wherein the quantity of solid acid catalyst required is also minimised.
It is another object of the invention to reduce the reaction time and temperature conditions for the isolation process.
It is another object of the invention to provide an improved process for the preparation of arteether which results in higher yield with 30:70 ratio of &agr;-&bgr;-isomers of arteether in the reaction product.
It is another object of the invention to provide an improved process for the preparation of arteether from dihydroartemisinin that is cost effective and economical.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of arteether from dihydroartemisinin, which comprises dissolution of dihydroartemisin in alcohol and adding a solid acid catalyst along with trialkylorthoformate in the reaction mixture, which produce higher yield of arteether, without chromatography. The solid acid catalyst can be reused in the process.
Accordingly, the present invention provides an improved process for the preparation of arteether, which comprises:
(a) dissolving dihydroartemisinin in dry ethanol;
(b) adding a solid acid catalyst with trialkylorthoformate in the reaction mixture;
(c) stirring the reaction mixture at room temperature for a period ranging from 1 to 10 hours;
(d) adding H
2
O to the reaction mixture and extracting the reaction product with a non-polar organic solvent, and
(e) drying the solvent in step (d) above over anhydrous sodium sulphate and evaporating the solvent to obtain pure arteether.
In an embodiment of the present invention, the sold acid catalyst is selected from p-toluenesulphonic acid, anhydrous AlCl
3
and cation exchange resins.
In a further embodiment of the invention, the dihydroartemisinin and the solid acid catalyst are used in a ratio of 1-2:1 w/w.
In another embodiment of invention, the trialkylorthoformate is selected from triethylorthoformate, trimethylorthoformate and other trialkylorthoformate.
In a further embodiment of the invention, the dihydroartemisinin and the trialkylorthoformate are used in the ratio of 10-25:1.
In another embodiment of the invention, ethanol is used as a solvent and the reactant.
In another embodiment of the invention, the reaction product is stirred at a temperature ranging between 20-40° C. and the ratio of &agr; and &bgr; arteether isomers obtained in the reaction product is &agr;:&bgr; arteether=20-30:80-70.
In another embodiment of the invention, the solid acid catalyst cation exchange resin can be regenerated and reused in the reaction.
DETAILED DESCRIPTION OF THE INVENTION
In the process of the invention, dihydroartemisinin is dissolved in absolute ethanol rather than benzene or anhydrous ether. In prior art processes, dihydroartemisinin was dissolved in the solvent benzene, which resulted in non-volatile impurities remaining in the product arteether after completion of reaction and work up. Benzene is also reported to be a carcinogenic in nature and is banned in some European countries. In the process
Bhakuni Rajendra Singh
Jain Dharam Chand
Kumar Sushil
Saxena Sudhanshu
Vishwakarma Ram Asrey
Council of Scientific and Industrial Research
Rotman Alan L.
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