Single pot conversion of artemisinin into artemether

Details Single pot conversion of artemisinin into artemether Single pot conversion of artemisinin into artemether

2002-03-25

2004-01-27

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06683193

ABSTRACT:

FIELD OF INVENTION
The present invention relates to an improved method for the preparation of Artemether. Artemether prepared from the process is useful for the treatment of uncomplicated, severe complicated and multi drug resistant malaria.
BACKGROUND OF THE INVENTION
Approximately, out of the 4 billion people suffering from malaria, 1-3 million, mostly children die every year worldwide. The rapidly spreading multidrug resistant parasite to standard quinoline based antimalarial drugs such as chloroquine and mefloquine based antimalarial complicate chemotherapy treatment of malaria patients.
Artemether is a methyl ether derivative of dihydroartemisinin. Dihydroartemisinin is derived from arternisinin, a novel sesquiterpene endoperoxide isolated from the plant
Artemisia annua
. Artemisinin and its derivative artemether, arteether, artelinate and artesunate a novel class of antimalarials derived from
Artemisia annua
are now proving their promising activity and being used for the treatment; of uncomplicated severe complicated/cerebral and multi drug resistant malaria.
Artemether, developed in France and China has undergone extensive preclinical, animal, toxicological studies as well as clinical studies. Artemether is more potential as compared to artemisinin and an antimalarial drug especially for treating multi drug resistant and complicated strains of
Plasmodium falciparum.
Artemether shows rapid shizonticidal action with quicker parasite clearance rate, short half life less side effect and low recrudence rate. Brossi, et al (Brossi, A; Venugopalan, B, Domingueg, G L; Yeh, H. J. C; Flippend-Anderson, J. L.; Buchs, P; Luo, X. D.; Milhous,W and peters, W; J. Med. Chem. 31, 646-649, 1988) reported the preparation of arteether, the ethyl ether derivative of dihydroartemisinin in two steps: First artemisinin was reduced with an excess of sodium borohydride in methanol at 0 to −5 degree C. in 3 hours to dihydroartemisinin in 79% yield. In the second step arteether is prepared by dissolving the dihydroartemisinin in the solvent mixture of benzene and ethanol at 45 degree C. followed by addition of BF
3
etherate and refluxing the reaction mixture at 70 degree C. for one hour. After completion of the reaction it was worked up, dried over anhydrous sodium sulphate with removal of the solvent dichloromethane. The reaction yielded arteether along with some impurities. Column chromatography of the reaction mixture over silica gel, 1:20 ratio yielded pure alpha and beta arteether in nearly qualitative yield.
EL-Feraly etal. (E L Feraly, F. S; Al-Yahya M A; Orabi, K. Y; Mc-Phail D R and Me Phail A. T. J.Nat.Prod. 55, 878-883 1992) reported the preparation of arteether by a process in which anhydrodihydroartemisinin, prepared from artemisinin was dissolved in absolute alcohol. The reaction mixture was stirred in the presence of p-toluene sulphonic acid used as a catalyst. On workup it yielded a mixture of beta arteether and C-11 epimer in the ratio of 3:1. In this process only beta arteether, is obtained and separation of 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).
In another method Bhakuni etal (Bhakuni, R. S.; Jain D. C and Sharma R. P. Indian. J. Chemistry, 34B, 529-30, 1995) arteether, artemether and other ether derivatives were prepared from dihydroartemisinin in different alcohol and benzene in the presence of chlorotrimethylsilane catalyst in 2-4 hours at room temperature. After workup of the reaction mixture and removal of the solvent, the impure reaction products were purified over silica gel column to obtained the pure mixture of alpha, beta ethers.
Another method is reported by Lin et al. (Lin, A. J. and Miller, R. E, J.Med Chero. 38,764-770, 1995) In this method the new ether derivatives were prepared by dissolving dihydroarternisinin in anhydrous ether and appropriate alcohol followed by BF
3
-etherate. The reaction mixture was stirred at room temperature for 24 hours. The yield of the purified products ranged from 40-90%. Purification was achieved by the use of silica gel chromatography.
Another method described by Jain et al (Jain D. C, Bhakuni R. S, Saxena S, kumar, S and Vishwakarma, R. A.) the preparation of arteether from artemisinin comprises: Reduction of artemisinin into dihydroartemisinin. Isolation of dihydroartemisinin. Acylation of dihydroartemisinin by dissolving it in alcohol and adding trialkylorthoformate in the reaction mixture, which produce ethers in quantitative yield in 10 hours at 40 degree C.
The above mentioned methods carry some disadvantages being less cost effective and more time consuming as compared to the present invention. Moreover, benzene, a carcinogenic solvent, used in the previous methods is not acceptable according to the health standard. Further, all the above methods require at least two separate steps to convert artemisinin into ethers i.e. reduction of the artemisinin into dihydroartemisinin in the first pot followed by isolation of dihydroartemisinin and then comes the second step of conversion of dihydroartemisinin into different ethers in the second pot. However, the present invention provide an efficient method for conversion of artemisinin into artemether.
OBJECTS OF INVENTION
The object of the present invention is the development of cost effective and improved single step method for the preparation of artemether which possesses reduction of artemisinin into dihydroartemisinin followed by methylation of dihydroartemisinin into artemether in a single pot.
SUMMARY OF THE INVENTION
The present invention provide a method for the preparation of artemether from artemisinin in one pot in just about 4 hours. It comprises: Reduction of artemisinin with less quantity of sodium borohydride in methanol at 0 to −5 degree C. into dihydroartemisinin which occurs without isolation of the methylated (metherified) product in the presence of solid/liquid acid catalyst in the same pot at room temperature. After usual workup, the impure artemether purified by silica gel column chromatography in 1:5 ratio, yielded 80-82% (w/w) pure alpha, beta artemether.


REFERENCES:
Haynes et al, Chem. Absract vol. 121 No. 238135, “Extrsaction of artemisinin and artemisnic acid”, 1994.

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