Single pot conversion of artemisinin into arteether

Details Single pot conversion of artemisinin into arteether Single pot conversion of artemisinin into arteether

2002-12-02

2004-06-15

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S348000, C549S354000

Reexamination Certificate

active

06750356

ABSTRACT:

FIELD OF INVENTION
The present invention relates to an improved single pot method for preparation of Arteether from Artemisinin. Arteether 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 people, 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.
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, a 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 (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° 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° C. followed by addition of BF
3
etherate and refluxing the reaction mixture at 70° C. for one hour. After the 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 equal qualitative yield.
E L-Feraly et al. (E L Feraly, F. S; Al-Yahya M A; Orabi, K. Y; Mc-Phail D R and Mc 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 Chem. 38,764-770,1995). In this method the new ether derivatives were prepared by dissolving dihydroartemisinin 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.
Yet another method described by Jain et al (Jain D. C, Bhakuni R. S, Saxena S, kumar, S and Vishwakarma, R. A. ref: U.S. Pat. No. 6,346,631, G.B. Application no 0007261.1 and German application no 10014669.4] teaches preparation of arteether from artemisinin which comprises: Reduction of artemisinin into dihydroartemisinin, isolation of dihydroartemisinin, conversion 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 are not cost effective and are time consuming. 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 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.
The Assignees co-pending U.S. application Ser. No. 10/105,964 filed on Mar. 25, 2002 which is incorporated herein as prior art reference teaches a process for preparing artemether from artemisinin. It should be noted that the aforesaid application does not use a polyhydroxy compound as catalyst during the process of reduction of artemisinin into dihydroartemisinin. In the present application, the applicants have utilized a polyhydroxy compound as a catalyst during the step of reduction of artemisinin to dihydroartemisinin. The Applicants have been successful in reducing artemisinin to dihydroartemisinin at room temperature in the presence of the polyhydroxy compound. It should be noted that to carry out a reaction not only the reactants play an inportant role but also other reaction conditions like solvent used, cooling or heating, inert atmosphere etc. are also important. Such reaction conditions provide a particular structure steriochemistry to the reactant molecules leading to the desired product. Introduction of the polyhydroxy compound for the reduction of artemisinin into dihydroartemisinin provides the ideal environment to the reactant molecules (artemisinin or the reducing agent or both) to reeact at room temperature (20-30° C.) which other react only at temperature in the range of 0-5° C. Also, the Applicants have found that the extraction of arteether from an aqueous reaction mixture using 1% ethyl acetate in n-hexane avoids extraction of unwanted polar impurities as compared to use of dihydromethane in the co-pending application. Further, the Applicants have found that resin could not perform esterification and hence, only unrecoverable catalysts such as chlorotrimethylsilane and p-toluene sulphonic acid are used in the present process. Thus the process of the present invention can not be considered as being obvious to a person of ordinary skill in the art and present invention provides an efficient method for conversion of artemisinin to arteether.
OBJECT OF INVENTION
The object of the present invention is the development of cost effective and improved single step method for the preparation of arteether which possesses reduction of artemisinin into dihydroartemisinin in the presence of a catalyst, conversion of dihydroartemisinin into arteether followed by extraction of the same in a single pot.
SUMMARY OF THE INVENTION
The present invention provides a method for the preparation of arteether from artemisinin in one pot in just about 4 ho

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