This application claims priority to Indian patent application no 3036/CHE/2010 filed on October 14, 2010 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to highly pure Lumefantrine having less than about 0.15 % of impurities. The present invention also relates to process for the preparation of pure Lumefantrine.

BACKGROUND OF THE INVENTION:

Lumefantrine (also called benflumetol, code no. CGP 56695; 1:1 racemate of the dextrogyre and levogyre enantiomers) is a fluorene derivative (2,3-benzindene). The compound was synthesized at the Academy of Military Medical Sciences, Beijing, China; published in Yaoxue Tongbao (1982), 17(1), 4-7, and has undergone preliminary clinical studies in China. Lumefantrine, in combination with Artemether (called coartem), was registered for the oral treatment of malaria in China in 1987.

Lumefantrine, chemically known as (±) 2-Dibutylamino-l-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol shown in formula I. It is marketed in combination with Artemether under the trade name COARTEM by Novartis.

Fomrula-I

COARTEM Tablets are for oral administration, having a fixed dose combination of Artemether and Lumefantrine in the ratio of 1:6. Each COARTEM Tablet contains 20 mg of Artemether and 120 mg Lumefantrine.

Chinese patent CN 1029680 discloses a process for the preparation of Lumefantrine, wherein 9H- fluorene is subjected to chlorination to give 2,7-dichloro-9H-fluorene; which on acylation using chloro acetyl chloride gives 2-Chloro-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanone; followed by condensation with dibutylamine to give 2-Dibutylamino-l-(2,7-dichloro-9H-fluorene-4-yl)-ethanol; and finally reacting with p-chlorobenzaldehyde. However the Lumefantrine is not obtained in pure form. PCT publication WO 2006117616 [Ranbaxy] discloses polymorphic form I of Lumefantrine and pharmaceutical compositions. It also describes a process for the preparation of Lumefantrine. The process includes treating 2-(dibutylamino)-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol with p-chlorobenzaldehyde in presence of NaOH and ethanol, cooling the reaction mixture to 10 °C; isolating Lumefantrine from the reaction mass; treating the reaction mass in a solvent followed by cooling to isolate Lumefantrine with 99.15%. Still there exists a need in the art for pure Lumefantrine.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide highly pure Lumefantrine having less than about 0.15 % of impurities.

Another aspect of the present invention is to provide Lumefantrine impurities having following structures.

In another aspect present invention provides, process for the purification of Lumefantrine comprising the steps of:
a) adding a solvent to Lumefantrine;
b) heating the solution;
c) optionally treating with charcoal; and
d) cooling the solution and filtered to isolate pure Lumefantrine.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides highly pure Lumefantrine having less than about 0.15 % of impurities. The present invention also relates to process for the preparation of highly pure Lumefantrine.

Accordingly, in one aspect the present invention provides, pure Lumefantrine having less than about 0.15 % of impurities or mixtures thereof selected from Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula I, Formula J, Formula K, Formula L, Formula M, Formula N, Formula O, Formula P, Formula Q, Formula R, Formula S, Formula T, Formula U, Formula V, Formula W, Formula X, Formula Y, Formula Z, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF.

The present invention also provide novel impurities selected form Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula I, Formula J, Formula K, Formula L, Formula M, Formula N, Formula O, Formula P, Formula Q, Formula R, Formula T, Formula U, Formula V, Formula W, Formula X, Formula Y, Formula Z and Formula IE.

In one embodiment he present invention provides, process for the purification of Lumefantrine comprising the steps of:

a) adding a solvent to Lumefantrine;
b) heating the solution;
c) optionally treating with charcoal; and
d) cooling the solution and filtered to isolate pure Lumefantrine.

According to the present invention, solvent is added to the crude Lumefantrine. The solvent is selected from aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, petroleum ether, preferably n-heptane; ester solvents such as ethyl acetate, propyl acetate or butyl acetate, preferably ethyl acetate; ketone solvents such as acetone methyl ethyl ketone or diethyl ketone, preferably acetone. The solution is heated to reflux
temperature to obtain clear solution. The obtained clear solution is optionally treated with charcoal and filtered under hot condition. The obtained filtrate is cooled to -5 to 10 °C, preferably 0-5 °C. The solid obtained is filtered, washed with a solvent selected from aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, petroleum ether, preferably n-heptane; ester solvents such as ethyl acetate, propyl acetate or butyl acetate, preferably ethyl acetate; ketone solvents such as acetone methyl ethyl ketone or diethyl ketone, preferably acetone and dried under vacuum to get Pure Lumefantrine.
In one embodiment, present invention provides the content of Formula A impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula B impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula C impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula D impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula E impurity in
Lumefantrine is less than 0.15%

In another embodiment, present invention provides the content of Formula F impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula G impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula H impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula I impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula J impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula K impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula L impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula M impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula N impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula O impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula P impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula Q impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula R impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula S impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula T impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula U impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula V impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula W impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula X impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula Y impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula Z impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula IA impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula IB impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula IC impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula ID impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula IE impurity in
Lumefantrine is less than 0.15 %.

In another embodiment, present invention provides the content of Formula IF impurity in
Lumefantrine is less than 0.15 %.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

Examples:

Example-1: 150 g of crude Lumefantrine was added to 500 lit of ethyl acetate and heated to reflux temperature. The obtained clear solution was treated with charcoal and filtered under hot .condition followed by washing with ethylacetate. The obtained filtrate was cooled to 0-5 °C, stirred for 3 hrs and filtered. The solid so obtained was washed with ethyl acetate and dried at 50 °c under vacuum to get 135 g of pure lumefantrine. Purity: 99.94%

Example-2: 112 g of crude Lumefntrine was added to 560 ml of n-heptane and heated to reflux temperature. The resulting clear solution was treated with charcoal and filtered under hot condition followed by washing 112 ml of n-heptane. The obtained filtrate was cooled to 0-5 °C, stirred for 3 hrs and filtered. The solid so obtained was washed with n-heptane and dried at 50 °c under vacuum to get 104 g of pure Lumefantrine. Purity : 99.9%

Example-3: 15 g of crude Lumefantrine was added to 75 ml of acetone and heated to 50-55 °C. The resulting clear solution was cooled to room temperature and stirred for 22 hrs; filtered and washed with acetone. The obtained solid was dried at 50 °c under vacuum to get 4.71g of pure Lumefantrine Purity : 99.7%

Example -4: Formula A.

To a stirred solution of aluminum chloride (1.7 g in aluminium chloride in 200 ml of dichloromethane) at -10° C was added 1.15 g of Chloroacetyl chloride and 2 g of 2,7-dichlorofluorene and stirred at same temperature. After confirming the absence of 2,7-dichlorofluorene, the reaction mass was quenched with dilute hydrochloric acid . The organic layer was concentrated, treated with methanol and filtered. The resulting filtrate was concentrated to isolate desired compound by column chromatography. (50 mg) M+ ion 386 obtained; HPLC RRT-0.80

Example-5: Formula B.

To a stirred solution of aluminum chloride (0.85 g of aluminum chloride in 100 ml of dichloromethane) at-10° C was added 0.752 g of dichloroacetyl chloride and lg of 2,7-Dichlorofluorene and stirred at same temperature. After confirming the absence of 2,7-Dichlorofluorene reaction mass was quenched with dilute hydrochloric acid . The organic layer was concentrated; filtered and the solid was isolated in Methanol. The crude obtained was subjected to column chromatography and eluted with 3 % methanol in chloroform to isolate desired compound. (50 mg) M+ ion 345 obtained

Example-6: Formula D

To a stirred solution of aluminum chloride (1.7 g of aluminum chloride in 20 ml of dichloromethane) at -10° C was added 1.15 g of chloroacetyl chloride and 2 g of 2,7-dichlorofluorene and stirred at same temperature. After confirming the absence of 2,7-dichlorofluorene, the reaction mass was quenched with dilute hydrochloric acid . The organic layer was concentrated under vacuum, treated with methanol and filtered. Thus, the obtained filtrate was concentrated and the crude obtained was subjected to column chromatography and eluted with 3 % methanol in chloroform to isolate desired compound. (50 mg)

M+ ion 585 obtained ; HPLC RRT-1.40

Example-7: Formula H

To a stirred suspension of 50 ml of butyraldehyde and lg, (0.0246 mol) of 4-[2-(dibutylamino)-l-hydroxyethyl]-2,7-dichloro-9H-fluoren-9-one was added 200 mg of sodium hydroxide and stirred at reflux temperature for 12 hours. The reaction mass was cooled to room temperature and diluted with ethyl acetate followed by washing with water. The organic layer was concentrated under vacuum to obtain of desired compound. The obtained crude was subjected to column chromatography and eluted with methanol in chloroform to isolate desired compound (20 mg) M+ ion 460 obtained; HPLO 71.32 %

Example-8: Formula I

To a stirred suspension of 5 ml of butyraldehyde and lg of 4-[2-(butylamino)-l-hydroxyethyl]-2,7-dichloro-9H-fluoren-9-one was added 0.2 g of sodium hydroxide and stirred at reflux temperature for 12 hours. After completion of the reaction, reaction mass was cooled to room temperature and diluted with ethyl acetate followed by washing with water. The organic layer obtained was concentrated under vacuum to obtain desired compound. M+ ion 404 obtained.

Example-9: Formula J

To a stirred suspension of 0.5 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(butylamino) ethanol and 10 ml methanol was added 0.11 g of sodium hydroxide, and the reaction mass was stirred at room temperature. After confirming the absence of starting material, the reaction mass was concentrated to obtain the desired compound. M+ ion 364 obtained.

Example-10: Formula K

To a stirred suspension of 0.5 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dipropylamino) ethanol and 10 ml of methanol was added 0.1 g of sodium hydroxide and stirred at room temperature. After confirming the absence of starting material the reaction mass was concentrated to obtain the desired compound. M+ ion 392 obtained

Example-11: Formula L

To a stirred suspension of 0.5 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(diethyl amino) ethanol and 10 of ml methanol was added 0.1 g of sodium hydroxide and stirred at room temperature. After confirming the absence of starting material the reaction mass was concentrated to obtain the desired compound. M+ ion 364 obtained.

Example-12: Formula M

To a stirred suspension of 0.5 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dimethylamino) ethanol and 10 ml of methanol was added 0.125 g of sodium hydroxide and stirred at room temperature,. After confirming the absence of starting material the reaction mass was concentrated to yield the desired compound. M+ ion 336 obtained.

Example-13: Formula N

To a stirred suspension of 0.5 g of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl) ethanone in methanol at -10° C was slowly added 0.024 g of sodium borohydride over a period of 30 minutes and stirred at same temperature. After confirming the absence of starting material by TLC, the reaction mass was concentrated atmospherically and was added dimethyl amine followed by stirring at room temperature. After completion of the reaction, the reaction mass was concentrated and isolated the desired compound in methanol.

Example-14: Formula S

To a stirred solution 0.2 g (0.0492 mol) of NaOH in 10 ml of methanol was added 1 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dibutylamino)ethanol and 0.34 g of benzaldehyde. The obtained suspension was stirred at reflux temperature until the absence of starting material was conformed by the TLC. After conforming the absence of starting material, the reaction mass was concentrated. The crude obtained was diluted with dichloromethane and washed with water. The organic layer was concentrated to isolate desired compound. M+ ion 494 obtained. HPLC RRT-0.82

Example-15: Formula T

To a stirred solution of 0.2 g of NaOH in 10 ml of methanol was added 1 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(butyl amino)ethanol and 0.4 g of benzaldehyde. The obtained suspension was stirred at reflux temperature until the absence of starting material was conformed by the TLC. After conforming the absence of starting material, the reaction mass was concentrated and the crude obtained was diluted with dichloromethane and washed with water. The organic layer was concentrated to yield desired compound. M+ ion 438 obtained.

Example-16: Formula IA

To a stirred suspension of 0.5 g of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl) ethanone in methanol at -10° C was slowly added 0.024 g of sodium borohydride over a period of 30 minutes and stirred at same temperature. After confirming absence of starting material by TLC, the reaction mass was concentrated atmospherically and was added 5 g of dipropyl amine and stirred at reflux temperature. After the formation of the desired compound, the reaction mass was concentrated and isolated in methanol. M+ ion 378 obtained.

Example-17: Formula IB

To a stirred suspension of 0.5 g of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl) ethanone in methanol at -10° C was slowly added 0.024 g of sodiumborohydride over a period of 30
minutes and stirred at same temperature. After confirming absence of starting material by
TLC, the reaction mass was concentrated and was added 5 g of diethyl amine and stirred at reflux temperature. After the formation of the desired compound, the reaction mass was concentrated and isolated in methanol.

M+ ion 350 obtained. HPLC RRT-0.43

Example-18: Formula IC

To a stirred suspension of 0.5 g of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dibutylamino) ethanol and 10 ml of methanol was added 0.125 g of sodium hydroxide and stirred at room temperature. After confirming the absence of starting material, the reaction mass was concentrated to isolate desired compound. HPLC-81.99 %; HPLC RRT-0.24 M+ ion 420 obtained

Example-19: Formula ID

To a stirred solution of 0.2 g of NaOH in 10 ml of methanol was added 1 g of 1 -(2,7-dichloro-9H-fluoren-4-yl)-2-(butyl amino)ethanol and 0.52 g of Para chloro benzaldehyde. The suspension obtained was stirred at reflux temperature until the absence of starting material was conformed by TLC. After conforming the absence of a starting material, the reaction mass was concentrated. The crude obtained was diluted with dichloromethane and washed with water and the organic layer was concentrated to yield the desired compound. HPLC-74.91 %

HPLC RRT-0.84 M+ ion 528 obtained.

Example-20: Formula IE

To a stirred solution of 1.97 g (0.0492 mol) of NaOH in 100 ml of methanol was added 10 g (0.0246 mol) of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dibutyl amino)ethanol and 5.24 g (.0372 mol) of meta chloro benzaldehyde. The suspension obtained was stirred at reflux temperature until the absence of starting material was conformed by TLC. After conforming the absence of a starting material, the reaction mass was concentrated. The crude obtained was diluted with dichloromethane and washed with water, and the organic layer was concentrated to obtain the desired compound (250mg). 1H NMR (300 MHz, CDC13): 5- 0.9 6H, 2.5 3.05H, 2.7 2.20H, 2.9 1.05H, 7.2 0.87H, 7.3 0.90H, 7.5 1.08H, 7.7 3.08H, 7.8 1.01H. HPLC-91.02% HPLC RRT-1.05 M+ ion 528 obtained.

Example-21: Formula IF

To a stirred solution of 1.97 g (0.0492 mol) of NaOH in 100 ml of methanol was added 10 g (0.0246 mol) of l-(2,7-dichloro-9H-fluoren-4-yl)-2-(dibutyl amino)ethanol and 5.24 g (0.0372)of orthochlorobenzaldehyde. The obtained suspension was stirred at reflux temperature until the absence of starting material was conformed by TLC. After conforming the absence of starting material, the reaction mass concentrated. The crude obtained was diluted with dichloromethane and washed with water and the organic layer was concentrated to yield the desired compound 250 mg.

1HNMR (300 MHz, CDCl3): 5= 0.9 6H, 2.5 3.13H, 2.7 2.08H, 2.9 1.01H, 7.2 0.94H, 7.3 0.94H, 7.5 1.08H, 7.7 4.02H, 7.8 1.08H. HPLC-93.96 % HPLC RRT-1.07 M+ ion 528 obtained.

Claims:

1. Pure Lumefantrine having less than 0.15 % of impurities.

2. The pure Lumefantrine according to claim 1, wherein the pure Lumefantrine having less than 0.15 % of impurities selected from the following compounds or mixtures thereof.

3. A compound of formula selected from:

4. A process for preparing pure Lumefantrine comprising the steps of:
a) adding a solvent to Lumefantrine;
b) heating the solution;
c) optionally treating with charcoal; and
d) cooling the solution and filtered to isolate pure Lumefantrine; wherein the solvent is selected from an aliphatic hydrocarbons, esters and ketones.

5. The process according to claim 4, wherein the solution of step b) is heated to reflux.

6. The process according to claim 4, wherein the solution of step d) is cooled to -5 to 10 °C.

7. The process according to claim 4, wherein the hydrocarbon solvent is n-heptane.

8. The process according to claim 4, wherein the ester solvent is ethyl acetate.

9. The process according to claim 4, wherein the ketone solvent is acetone.