This application claims priority to Indian patent application No 2820/CHE/2009 filed on,
November 17, 2009 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Anti malarial drugs Dihydroartemisinin hemisuccinate and artemether from artemisinin.

BACKGROUND OF THE INVENTION

The sesquiterpene endoperoxide lactone artemisinin and its 10a derivative dihydroartemisinin hemisuccinate are used in chemotherapy against ordinary and severe (acute) infections with Plasmodium falciparum, which is responsible for 85% of malarial illnesses. The chemistry and the antiprotozoal action of these compounds is described in the following publications: H. J. Woerdenbag et al., Progress in the Research of Artemisinin-related Antimalarials: An Update, Pharm. World Sci. 16 (4), 169-180 (1994); T. T. Hien et al., Qinghaosu, The Lancet 341, 603-608 (1993); A. R. Butler et al., Artemisinin (Qinghaosu): A New Type of Antimalarial Drug, Chem. Soc. Reviews 85-90 (1992); S. S. Zaman et al., Some Aspects of the Chemistry and Biological Activity of Artemisinin and Related Antimalarials, Heterocycles 32 (8), 1593-1638 (1991); H. J. Woerdenbag et al., Artemisia annua L.: a Source of Novel Antimalarial Drugs, Pharm. Weekblad Sci. 12 (5), 169-181 (1990); D. L. Klayman, Qinghaosu (Artemisinin): An Antimalarial Drug from China, Science 228, 1049-1055 (1985).

Dihydroartemisinin hemisuccinate (Artesunate or artesunic acid) & Artemether are structurally represented by Formula-I and Formula II respectively.

Dihydroartemisinin hemisuccinate was synthetically prepared for the first time by Chinese scientists at the end of 1979 to the beginning of 1980.

Acta Pharm.Sin. 16 (6), 429-439 (1981) describe the preparation of dihydroartemisinin hemisuccinate by acylation of dihydroartemisinin with succinic anhydride in pyridine. This publication discloses the process to obtain the dihydroartemisinin hemisuccinate in a yield of 60% by means of warming dihydroartemisinin and succinic anhydride in pyridine at 30 °C for 24 hours.

Another process for the preparation of Artesunate was disclosed in Acta Chim. Sinica 40 (6), 557-561 (1982). In this publication ester derivatives of dihydroartemisinin is 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%.

US patent 5654446, 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.

US patent 6677463, describes single pot synthesis for the preparation of Artesunate from artemisinin. This patent discloses reduction of artermisinin to dihydroartemisinin in presence of polyhydroxy compound and sodium borohydride. After completion of reaction succinic anhydride and anion exchange resin is 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 96 % of pure Artesunate. The process is complex and time consuming as it involves chromatographic purification step.

PCT publication WO 2008087667 describes process for the preparation of Artesunate from Artemisinin. This application discloses reduction of artermisinin to dihydroartemisinin with a mixture of dihydroxy compound and sodium borohydride in a solvent mixture consisting of an aprotic solvent and isopropanol. Dihydroartemisinin is esterified in the presence of succinic anhydride and Imidazole or its derivative as a catalyst in an aprotic solvent and Artesunate isolated by crystallization from crude product.

The above mentioned methods yield Artesunate having impurities. So there is a continuing need to prepare Artesunate with high purity with cost effective.

Thus the present invention provides Artesunate with high purity, cost effective and commercially viable process.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for the preparation of Artesunate from Artemisinin comprising the steps of: a) Reducing Artemisinin to dihydroartemisinin; b) esterifying in the presence of 4-Dimethylamino pyridine with succinic anhydride; c) adjusting the pH to basic with a base; d) removing the impurities; and e) isolating pure Artesunate by adjusting pH to acidic.

One more object of the present invention is to provide crystalline Artesunate.
Another object of the present invention is to provide an improved process for the preparation of Artemether from dihydroartemisinin comprising the steps of: a) adding dichloromethane to Dihydro artemisinin; b) adding mixture of methanol and HC1; c) adding a base; and d) purifying crude Artemether in methanol to obtain purified Artemether.

One more object of the present invention is to provide crystalline Artemether.

DESCRIPTION OF THE DRAWINGS

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :

Figure 1: illustrates the PXRD spectra of Artesunate

Figure 2: illustrates the PXRD spectra of Artemether

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to process for the preparation of Antimalarials such as Dihydro artemisinin, Artesunate and Artemether.

In one aspect the present invention provides, process for the preparation of Artesunate from Artemisinin comprising the steps of:

a) reducing Artemisinin to dihydroartemisinin;
b) esterifying in the presence of 4-Dimethylamino pyridine with succinic anhydride;
c) adjusting the pH to basic with a base;
d) removing the impurities; and
e) isolating pure Artesunate by adjusting pH to acidic.

In one embodiment of the present invention, the reduction of Artemisinin into Dihydroartemisinin in step-a is carried out in presence of metalhydides such as sodium borohydride in a solvent such as methanol at low temperatures -5 to +10 °C, preferably -5 to +5 °C and more preferably at -3 to +5 °C.

In one more embodiment of the present invention, the base used in the step-c is selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkali metal carbonates such as sodium carbonate and potassium carbonate, preferably sodium hydroxide.
In another embodiment of the present invention, the impurities in the step-c is removed by washing the reaction mixture with water immiscible organic solvents like toluene, Dichloromethane, and ethyl acetate, preferably ethyl acetate.

In one more embodiment of the present invention, acid used for adjusting the pH to isolate pure Artesunate, is organic acid or inorganic acid. The organic acid is selected from acetic acid or trifluoro acetic acid, preferably acetic acid. The inorganic acid is selected from hydrochloric acid or hydrobromic acid, preferably hydrochloric acid.

In one more embodiment of the present invention, the alkaline metal salt of Artesunate is optionally isolated and converted into Artesunate.

As per the present invention, Artemisinin is reduced into dihydroartemisinin in presence of sodium borohydride and methanol at low temperatures -5 to +10 °C. The obtained dihydroartemisinin is esterified in the presence of 4-Dimethylamino pyridine with succinic anhydride. pH of the reaction mixture is adjusted with a base selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkali metal carbonates such as sodium carbonate and potassium carbonate, preferably sodium hydroxide. Impurities are removed by washing the reaction mixture with water immiscible organic solvents like toluene, Dichloromethane and ethyl acetate, preferably

ethyl acetate. Pure Artesunate is isolated by adjusting the pH to acidic by using organic acids selected from acetic acid or trifluoro acetic acid preferably acetic acid.
In one more aspect of the present invention provides, Crystalline Form of Artesunate.

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/9 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Accordingly, the present invention provides crystalline Artesunate characterized by Powder X-ray diffraction pattern as shown in figure 1, comprising peaks at about 9.3, 9.5, 12.2, 12.9, 15.4, 18.5 and 19.8± 0.2 20.

In another aspect the present invention provides, process for the preparation of Artemether from dihydroartemisinin comprising the steps of:

a) adding halogenated solvent to Dihydroartemisinin;
b) adding mixture of methanol and HC1;
c) adding a base; and
d) purifying crude Artemether in methanol to obtain pure Artemether.

In one embodiment of the present invention, halogenated solvent used in the step-a is selected from dichloromethane, chloroform, 1,2-dichloroethane,. preferably dichloromethane.

In one embodiment of the present invention, the base used in the step-c is taken from sodium bicarbonate and potassium carbonate preferably sodium bicarbonate.

As per the present invention, dichloromethane is added to Dihydro artemisinin and to this, mixture of methanol and HC1 is added and stirred. To this reaction mixture sodium bicarbonate is added to obtain crude Artemether. The obtained Artemether is purified in methanol to obtain pure Artemether.

In another aspect the present invention provides, Crystalline Form of Artemether.
In one embodiment, crystalline Artesunate is characterized by Powder X-ray diffraction pattern as shown in figure 2, comprising peak at about 9.6± 0.2 20.

In one embodiment, the present invention provides Artesunate having a D90 particle size less than 350 um.

In one more embodiment, the present invention provides Artemether having a D90 particle size less than 400 um.

As per the present invention, the particle size of Artesunate and Artemether are summarized in the following table.

The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in anyway.

Example-1
Process for the preparation of Dihydro artemisinin
Methanol (400 ml) was added to Artemisinin (100 g) and the reaction mixture was cooled to room temperature. To this sodium borohydride (13.4 g) was added at a temperature of -3 to +5 °C and the reaction mixture was stirred for 2-3 hours at 0-5 °C. To this reaction mixture dilute acetic acid (88 ml) was added and cooled to 0 to -10 °C. DM water (1600 ml) was added to the reaction mixture and solid was filtered. The obtained filtrate was washed with DM water and dried to yield Dihydro artemisinin.

Example-2
Process for the preparation of Artesunate
To the Dihydro artemisinin (100 g) obtained in the Example-1, tetrahydrofuran (200 ml) was added and to this succinic anhydride (45.8 g) and 4-Dimethylaminopyridine (4.3 g) was added and the reaction mixture was stirred for 2-3 hours at 45-50 °C. The reaction mixture was cooled to room temperature and DM water (1000 ml) was added. The pH of the reaction mixture was adjusted to 8.5-9.0 by adding sodium hydroxide solution (60 ml). The reaction mixture was stirred for Vz hour to get clear solution and filtered through hyflo bed. The aqueous reaction mixture was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 5.0-5.5 by the addition of acetic acid (80 ml). The product was extracted with dichloromethane (1500 ml). The combined organic layers were washed with DM water (500 ml) and completely distilled under vacuum. To the residue methanol was added and cooled to room temperature. To this carbon (5 g) was added and stirred at room temperature and filtered through hyflo bed. To the filtrate water (500 ml) was added dried under vacuum for 10-12 hours to yield Artesunate.

Example-3
Process for the preparation of Artemether
To the Dihydro artemisinin (100 g) obtained in the Example-1, dichloro methane (1200 ml) was added and the reaction mixture was stirred for 5 min at room temperature. To this mixture of methanol (94 ml) and CP HC1 (6.63 g) was added stirred for 4 hours at room temperature. The reaction mixture was cooled to 25-10 °C, and a solution of sodium bicarbonate (6.25 g) in DM water (150 ml) was added. The layers were separated and the aqueous phase was extracted with dichloromethane (200 ml). The combined organic layers were washed with DM water and organic layer was completely distilled under vacuum. To this methanol (200 ml) was added. Once again organic layer was completely distilled under vacuum and methanol (400 ml) was added to the obtained crude. To this reaction mixture PS-130 Carbon (4 g) was added and stirred for '/2 hour at room temperature. The reaction mixture was filtered and washed with methanol (100 ml). To this filtrate water (500 ml) was added and solid was filtered and to this methanol (500 ml) was added. To the reaction mixture water was added and stirred for 1-2 hours. Solid was filtered and dried to yield Crude Artemether.

Purification of crude Artemether
Artemether crude (64 g) was dissolved in methanol (320 ml) and stirred for 10-15 min to obtain clear solution. To this reaction mixture DM water (320 ml) was added and stirred at room temperature for 2-3 hours. The solid was filtered and washed with 1:1 methanol/water mixture (128 ml). The solid was dried under vacuum to yield pure Artemether.

We claim:

1. An improved process for the preparation of Artesunate from Artemisinin
comprising the steps of:

a) reducing Artemisinin to dihydroartemisinin;
b) esterifying in the presence of 4-Dimethylamino pyridine with succinic anhydride;
c) adjusting the pH to basic with a base;
d) removing the impurities; and
e) isolating pure Artesunate by adjusting pH to acidic.

2. The process according to claim 1, wherein the reduction of Artemisinin to dihydroartemisinin is carried out by using metal hydrides such as sodium borohydride.

3. The process according to claim 1, wherein the base is selected from alkali metal hydroxides or alkali metal carbonates.

4. The process according to claim 1, wherein the impurities are removed by washing the reaction mixture with water immiscible organic solvent.

5. Crystalline Artesunate.

6. The crystalline Artesunate according to claim 5, wherein crystalline Artesunate is characterized by a powder X-ray diffraction pattern having peaks at 9.3, 9.5, 12.2, 12.9, 15.4, 18.5 and 19.8± 0.2 2G.

7. An improved process for the preparation of Artemether from dihydroartemisinin comprising the steps of:

a) adding halogenated solvent to Dihydroartemisinin;
b) adding mixture of methanol and HC1;
c) adding a base; and
d) purifying crude Artemether in methanol to obtain pure Artemether.

8. The process according to claim 7, wherein the base is selected from sodium
bicarbonate or potassium carbonate.

9. Crystalline Artemether.

10. The crystalline Artemether according to claim 9, wherein crystalline Artesunate is characterized by a powder X-ray diffraction pattern having peak at 9.6± 0.2 20.