FIELD OF INVENTION
The present invention relates to a novel process for preparing an antimalarial drug commonly known as lumefantrine.

BACKGROUND OF THE INVENTION

Lumefantrine is a synthetic racemic fluorene derivative, was synthesized originally by Academy of Military Medical Sciences in Beijing, China and is used to treat malaria including the stand by-emerging treatment of adults and children with infections due to Plasmodium falciparum, which is responsible for producing severe complications and cerebral malaria, which can cause the patient to lapse into coma and ultimately to death. Lumefantrine has emerged as a new drug for the treatment of chloroquine resistant, pernicious malignant malaria.

Lumefantrine is only used in combination with artemether. The combination of lumefantrine and artemether known as "Coartem" and "Riamet", an artemisinin-based combination therapy (ACT) indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria.

The chemical name of Lumifantrine is 2-(dibutylamino)-l-[(9Z)-2,7- dichloro-9-(4-chlorobenzylidene)-9H-fiuoren-4-yl]ethanol which is represented by formula I. 2-Dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II is a an advance intermediate in preparation of lumefantrine of formula I.

The process for its preparation is well described in the literature.Chinese patent CN1042535 discloses the synthesis of lumefantrine as shown in Scheme I. The synthesis involves preparation of 2,7-dichlorofluorene-4-chloroethanone, which is reduced to 2-(2,7-dichloro-9-fluoren-4-yl)oxirane using potassium borohydride as a reducing agent to form oxirane intermediate. The oxirane intermediate is then treated with dibutylamine in presence of a base to form 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol. This is reacted with p-chlorobenzaldehyde in ethanol in presence of sodium hydroxide to give lumefantrine of formula I. The condensation of dibutylamine in presence of a base forms an unwanted impurity which reduces the yield and purity of the final compound lumefantrine.

CN1865227 describes the preparation of lumefantrine in which dibutylamine magnesium bromide is used for condensation instead of dibutylamine. In this process the use of Grignard reagent makes the process cumbersome due to its hazardous nature and handling problem. Moreover, Grignard reaction involves dry reaction conditions where a costly dry solvent have to be employed.

Organic Process Research and Development 2007, 11, 341-345 describes a process for preparation of lumefantrine as shown in below reaction scheme-II. The process involves, chlorinating 9H-fluorene in acetic acid forms a mixture of 2,7-dichloro-9H-fluorene and 2,5-dichloro-9H-fluorene. The chloroacylation of obtained 2,7-dichloro-9H-fluorene using aluminium chloride and chloroacetyl chloride in dichloromethane. The reaction mixture is quenched with diluted hydrochloric acid to form compound 5. Reducing compound 5 using sodium borohydride in ethanol to form chlorohydrin compound 6, insitu converting compound 6 into epoxide compound 7 using sodium methylate. Ring opening reaction of epoxide 7 with an excess of dibutylamine in ethanol to form compound 8. Converting compound 8 into compound 9 and compound 2 via a Knoevenagel-type condensation, the desired Z-isomer i.e, compound 2 is isolated and recrystallized from 2-propanol.

The above article describes another alternative process for preparation of lumefantrine as shown in below reaction scheme-Ill. The process involves chlorinating 9H-fluorene in acetic acid forms a mixture of 2,7- dichloro-9H-fluorene and 2,5-dichloro-9H-fluorene; the chloroacylation of obtained 2,7-dichloro-9H-fluorene using aluminium chloride and chloroacetyl chloride in dichloromethane; quenching the reaction mixture with diluted hydrochloric acid to form compound 5; reducing compound 5 using sodium borohydride in ethanol to form chlorohydrin compound 6; converting compound 6 insitu into compound 8 using sodium hydroxide; and then further conversion of compound 8 into compound 2 as explained in above scheme -II.

The prior arts mentioned herein thus suffer from several drawbacks. Most of the processes described above are silent about the purity of the Z-isomer and the reaction time is very lengthy sometimes as lengthy as 60 hours. Even though the Organic Process Research and Development article claims as an improved manufacturing process with short cycle time for isomerisation and crystallization, this process also suffers from some major drawbacks. The process requires heating to get the temperature from 23° C to 70°C within one hour and immediately cooling back to temperature 38°C, which is followed by agitation for at least four hours to complete crystallization. As noted above, while carrying out the process in large scale, it is very difficult to get consistent results. Also the volume of the solvent used in this process is as large as 15 times that of input. Also, during preparation of the advanced intermediate there is isolation of compound 5 which is highly lachrymetric and the isolation method is not suitable for bulk production.

Hence there is a need to develop a robust and environment friendly process for the preparation of lumeifantrine in general and a process of preparation of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II in particular which gives high yield, high purity and reduces the reaction time significantly. The inventors of the present invention developed an improved process for the preparation of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol, which overcomes most of the drawbacks in the prior arts and avoids the use of a base for the condensation of dibutylamine. The present invention also provide an improved process for the preparation of Lumefantrine of formula I which reduces the reaction time as well as the isomerization time to get pure Z-isomer.

The process of the present invention is cost effective overcomes most of the above stated drawbacks.

SUMMARY OF THE INVENTION

The principal aspect of the present invention is to provide a process for the preparation of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II, which comprises:

a) chloroacylating 2,7-dichloro-9H-fluorene of formula V using chloroaetyl chloride and a catalyst in presence of an organic solvent to form 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of formula IV;

b) reducing 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of formula IV using a suitable reducing agent and an alcoholic solvent to form 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol of formula III; and

c) condensing 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol of formula III obtained in step b) with di-n-butyl amine in presence of a buffer to give 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II.

The another aspect of the present invention is to provide a process for the preparation of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol of formula I comprising reacting 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II with p-chlorobenzaldehyde in presence of solvent while maintaining the stirrer speed at more than 90 rpm to form 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol of formula I.

The process of the present invention may be illustrated by the below reaction scheme -IV:

The another aspect of the present invention is to provide a novel crystalline form of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II characterized by prominent XRD peaks at 20 values 9.44, 9.84, 18.91,23.75, 26.05, and 29.59±20.

The another aspect of the present invention is to provide a novel crystalline form of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol of formula I characterized by prominent XRD peaks at 20 values 5.55,11.13, 20.14 and 23.O8±20.

BRIEF DESCRIPTION OF THE FIGURE

Figure 1: X-Ray diffractogram of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene- 4-yl]ethanol Figure 2: X-Ray diffractogram of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol

Figure 3: DSC thermogram of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yljethanol

Figure 4: DSC thermogram of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol

Figure 5: Microscopic data (4x magnification) of 2-(dibutylamino)-l-[(9Z)-2,7- dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol

Figure 6: PSD crystogram of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fiuoren-4-yl]ethanol.

DETAIL DESCRIPTION OF THE INVENTION

Accordingly in an embodiment of the invention, chloroacylation in step (a) is carried out in presence of an organic solvent selected from methylene dichloride, ethylene dichloride, ethyl acetate, toluene, benzene, xylene, N,N-dimethyl formamide (DMF), tetrahydrofuran (THF) and the like, preferably methylene dichloride and a catalyst preferably a Lewis acid selected from the group consisting of aluminium chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, and sulphuric acid, preferably aluminium chloride at a temperature in the range of -10 to 10° C, preferably 5±2° C.

In another embodiment of the invention, reduction in step (b) is carried out in presence of a reducing agent selected from Lithium aluminium hydride, Sodium amalgam, Sodium borohydride etc. preferably Sodium borohydride and an alcoholic solvent selected from selected from methanol, ethanol or propanol, preferably methanol at the temperature range of -10 to 25 °C preferably at 0-10° C to obtain compound of formula IV.

In yet another embodiment of the invention, condensation in step (c) is carried out in presence of a buffer selected from sodium citrate, sodium acetate, mono potassium phosphate, ammonium acetate etc. preferably sodium acetate.

In another embodiment of the invention, the chloroacylation, reduction and condensation are carried out insitu to obtain 2-dibutylamino-l-[2,7-dichloro-9H-fiuorene-4-yl]ethanol of formula II.

In yet another embodiment of the invention, reaction of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II with p-chlorobenzaldehyde is carried out using a solvent preferably an alcoholic solvent selected from methanol, ethanol or propanol, more preferably methanol at a temperature in the range of 40 to 100°C preferably at 60-80°C to obtain lumefantrine of formula I.

In still another embodiment of the invention, Z-isomer of lumefantrine is prepared by doing reaction in 4 volumes of methanol at more than 75 rpm preferably on or above 90 rpm. Further the crude Z-isomer is taken in ethyl acetate heated to 65°C and water washed at this temperature and slowly cooled to get crystalline Lumefantrine with 99.5% HPLC purity having unknown single impurity not more than 0.1%.

In still another embodiment of the invention, the crystalline form of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II is novel and stable and characterized by having prominent XRD peaks at 20 values 9.44, 9.84, 18.91, 23.75, 26.05, and 29.59±20 substantially similar to the diffractogram given in figure 1. This novel crystalline form is further characterized by DSC peak at 78.47°C as given in Figure 3.

In still another embodiment of the invention, the crystalline form of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol of formula I is novel, thermodynamically stable and the crystals are free flowing which is highly desired for pharmaceutical preparation. This novel crystalline form of lumefantrine is characterized by having prominent XRD peaks at 20 values 5.55, 11.13, 20.14 and 23.O8±2θ and having diffractogram pattern as given in figure 2. This is further characterized by DSC peak at 133.45°C as given in Figure 4. This novel crystalline form of lumefantrine is further characterized by microscopic analysis as shown in figure 5. The particles are crystalline in nature, the size varies from 238 μm to 423 μm, and overlapping and majority are hexagonal in shape.

In still another embodiment of the invention the particle size distribution of lumefantrine obtained by this invention is d10= 7.57 μm, d5o=40.64 μm and d90=143.79um. The PSD is further characterized by the histogram shown in Figure 6. The particle size obtained by the present invention is highly desirable for pharmaceutical preparation because of the optimum size for getting the best possible bioavailability of the formulated drug product.

The Lumefantrine obtained by the present invention has following advantages:

1. The process is a one pot synthesis from 2,7-dichloro-9H-fiuorene to 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol without isolating any of the intermediates. The 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone intermediate which is highly lachrymetric is taken for reduction as such in methylene chloride and methanol mixture without isolating.

2. The use of buffer for the condensation of dibutylamine reduces drastically the formation of impurities.

3. The process is highly selective and produces specially z-isomer of lumefantrine.

4. The lumefantrine obtained from the developed purification process is free-flowing and suitable for formulation.

5. Overall time cycle is drastically reduced in intermediate as well as in lumefantrine preparation.

The present invention is illustrated by the following examples, which are not to limit the scope of the invention.

Example:

a) Preparation of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yI)ethanone:

Methylene dichloride (700 L) and anhydrous aluminium chloride (84.5 kg) were charged into the flask at 30 ±2°C. Chloroacetyl chloride (59 kg) was slowly added, cooled to 5±2°C under nitrogen atmosphere. 2,7-Dichloro-9H-fluorene(100 kg) was added in lots and stirred. After completion of reaction, the reaction mass was slowly quenched into DM water at 0-20°C. The reaction mass was allowed to attain 30±2°C under stirring for 2 hrs. Two layers were separated and aqueous layer was extracted with methylene dichloride. All methylene dichloride layers were combined and washed with 5% sodium hydroxide solution at 30±2°C under nitrogen atmosphere. Two layers were separated. All MDC layer was combined and washed with DM water. The pH of aqueous layer should be less than 7. Methylene dichloride was distilled out to residual volume two.

b) Preparation of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol:
Methanol (500 L) was charged to the above reaction mass below 50°C,
cooled to 0-10°C. Sodium borohydride (5.6 kg) was slowly added in lots by maintaining temperature 0-10°C and stirred for 2 -4 hours.

c) Preparation of 2-diburyIamino-l-[2,7-dichloro-9H-fluorene-4- yl]ethanol:
Di-n-butyl amine (82.24 kg) and Sodium acetate (17.41 kg) was added to the above reaction mass and heated to remove methylene dichloride. Further reaction mass stirred at 80±2°C under pressure (1-1.5 Kg/cm2) for 6 hours. After reaction completion, reaction mixture was cooled to 30 to 35°C. The reaction mass was stirred for 3 hours at 0-5°C, filtered and suck dried. Ethyl acetate (250 L) and above wet material was charged into the flask and heated to 60-65 °C for getting clear solution. DM water (400 L) was added at 60 to 65°C, stirred for 30 minutes at 60 to 65°C. Two layers were separated and ethyl acetate layer was cooled to 0°C and stirred for 2 hours, filtered, and suck dried.

Yield: 115 ±2 Kg.

d) Preparation of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol:

Methanol (400ml) and p-chlorobenzaldehyde (40g) were charged into a flask containing 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol (l00g) at 30±2°C, stirred for 30 minutes. Sodium hydroxide (12g) was added, heated to 70± 2°C and stirred at RPM more than 75 for 2 hours. After reaction completion, reaction mass was stirred at RPM more than 75 for 4 hours, cooled to 0-5 °C and stirred for 1-2 hours. The product was centrifuged at 0-5°C, spin dried for 1 hour and solids are washed with chilled methanol (100ml) and DM water.

The wet material is dissolved in Ethyl acetate (650ml) and washed three times with DM water at 65°C Two layers were separated. The organic layer was filtered through sparkler filter at 65±2°C, washed with ethyl acetate (100ml) at 65±2°C. The reaction mass was heated to 75±2°C maintained for one hour. The aqueous layers were separated and ethyl acetate was distilled out to residual volume 3.5-3.8. The reaction mass was heated to 65°C, maintained till reaction mass becomes clear and stirred for 30 minutes. The reaction mass was cooled to 56°C, over a period of 3-4 hours, and maintained at 56°C for 4 hours during which precipitation of crystals completes and further cooled slowly to 26±2°C. The reaction mass was stirred for 1-2 hours at 26°C.The product was centrifuged, spin dried for 2 hours and the solids are washed with chilled ethyl acetate. The product was dried at 50-55 °C under vacuum.

Yield = 1.2 w/w

We claim:

1. A process for the preparation of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II, which comprises:

a) chloroacylating 2,7-dichloro-9H-fluoreneof formula V using chloroaetyl chloride and a catalyst in presence of an organic solvent to form 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of formula of formula IV;

b) reducing 2-chloro-1 -(2,7-dichloro-9H-fluoren-4-yl)ethanone of formula IV using a suitable reducing agent and an alcoholic solvent to form 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol of formula III; and

c) condensing 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol of formula III obtained in step b) with di-n-butyl amine in presence of a buffer to give 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II.

2. A process according to claim 1, wherein the catalyst in step (a) is a Lewis acid selected from the group consisting of aluminium chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride and sulphuric acid, preferably aluminium chloride.

3. A process according to claim 1, wherein solvent in step (a) is selected from methylene dichloride, ethylene dichloride, monochlorobenzene, N,N-dimethyl formamide, tetrahydrofuran and the like, preferably methylene dichloride.

4. A process according to claim 1, wherein reducing agent in step (b) is selected from Lithium aluminium hydride, Sodium amalgam, Sodium borohydride etc. preferably Sodium borohydride.

5. A process according to claim 1, wherein an alcoholic solvent in step (b) is selected from methanol, ethanol or propanol, preferably methanol.

6. A process according to claim 1, wherein buffer in step (c) is selected from sodium citrate, sodium acetate, mono potassium phosphate, ammonium acetate, preferably sodium acetate.

7. A process for preparation of 2-(diburylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol of formula I comprising reacting 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol of formula II with p-chlorobenzaldehyde in presence of an alcoholic solvent selected from methanol, ethanol propanol or butanol, preferably methanol, while maintaining the stirrer speed at more than about 90 rpm.

8. A process according to claim 1, wherein lumifantrine is purified by ethyl acetate by giving water washes at high temperature and slow crystallization.

9. A crystalline form of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol characterized by having prominent XRD peaks at 29 values 9.44, 9.84, 18.91, 23.75, 26.05, and 29.59±29.

10. A crystalline form of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol according to claim 9, wherein the XRD diffractogram is substantially same as given in figure 1.

11. A crystalline form of 2-dibutylamino-l-[2,7-dichloro-9H-fluorene-4-yl]ethanol according to claim 9, wherein the DSC peak is at 78.47°C as given in Figure 3.

12. A crystalline form of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9/f-fluoren-4-yl]ethanol characterized by having prominent XRD peaks at 2θ values 5.55, 11.13, 20.14 and 23.O8±2θ.

13. A crystalline form of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol according to claim 12, wherein the XRD diffractogram is substantially same as given in figure 2.

14. A crystalline form of 2-(dibutylamino)-l-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol according to claim 12, wherein the DSC peak is at 133.45°C as given in Figure 4.

15.2-(Dibutylamino)-1 -[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-
fluoren-4-yl]ethanol prepared according to claim 7, wherein the particle size distribution d10= 7.57 μm, d50=40.64 μm and d90=143.79μm and/or the PSD is further characterized by the histogram shown in Figure 6.