Title of Invention

PROCESS FOR THE SYNTHESIS OF LUMEFANTRINE

Abstract

Disclosed herein is an improved process for the synthesis and purification of antimalarial drug Lumefantrine involving Grignard reaction. The process comprises condensation of 2,7-dihloro-9H-fluorene-4oxiran with p-chloro benzaldehyde to yield 2,7-dichloro -9(4-chloro benzylidine) fluorine-4-oxirane; reaction of 2,7-dichloro -9(4-chloro benzylidine) fluorine-4-oxirane with a Grignard reagent of Formula IV in suitable organic solvent and isolation of lumefantrine from a suitable organic solvent.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule!3) TITLE OF THE INVENTION: "Improved synthesis of antimalarial drug" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical field of the Invention The present invention relates to an improved process for the synthesis and purification of antimalarial drug involving Grignard reaction. Background of the Invention Lumefantrine (formerly known as benflumetol of Formula -I), was synthesized originally by Academy of Military Medical Sciences in Beijing, China. It is a racemic fluorene derivative with the chemical name 2-dibutylamino-l-[2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]-ethanol. Malaria, transmitted by the Anopheles mosquito and caused by protozoa of the Plasmodium genus is a disease, which occurs in about 100 million people each year, and almost a million people die every year, mortality is more among children under 5 years of age who are especially sensitive because of their lack of immunity to the disease. There exist various forms of malaria Malaria tropica (caused by plasmodium falciparum), Malaria tertiana (caused by plasmodiumvivax or plasmodium ovale) and Malaris quartana (caused by plasmodium malariae). Malaria tropica is the most severe form of the disease, which is responsible for producing severe complication and celebral malaria, which can cause the patient to lapse into coma and ultimately to death. Severe P. falciparum infections are common in both rural and urban areas and the management of these cases has become difficult because of emerging problem of drug resistant infections. Lumefantrine has emerged as a new drug for the treatment of chloroquine 2 resistant, pernicious malignant malaria. The synthesis of lumefantrine was disclosed in Chinese patent CN 1042535 (1990). (Published on 30 May 1990), Atkinson et al J. Med. Chem. 11,1223(1968) and Atkinson et al., J. Med. Chem. 17, 1009 (1974). (Scheme I) cr ^ ^ ^ ci cr 2,7 dichlorofluorene FLUORENE Lumefantrine (I) NaOH/ p-chloro benzahdehyde The compound of formula II is reacted with dibutyl amine resulting in compound of Formula III which is further reacted with p-chloro benzaldehyde in ethanol in presence of sodium hydroxide for 24 hrs to give lumefantrine. The disadvantage of the prior art process is that reaction of compound of formula II with p-chloro benzaldehyde is very sluggish, the reaction does not go to completion even after 2 days and the starting material remains to the extent of about 5%, also the reaction generate lot of impurities (clearly seen on TLC), the resulting product has to be purified repeatedly to achieve a purity level acceptable for pharmaceutical use. This results in yield loss making the process cumbersome and uneconomical. Also the process for the preparation of 2,7 dichloro fluorene as disclosed in the prior art, involves the use of chlorine gas, using this process monchloro and trichoro impurities are formed resulting in a low yield of the product about 40%, hence there is a need for a process which generates 3 less impurity and provide good yield. The yield of 2,7, dichloro fluorene will subsequently affect overall yield of lumefantrine in the process. And also there is need for an industrially viable process for the synthesis of lumefantrine, which generates less impurity and increased efficiency. Object of the Invention The object of the present invention is to provide an improved process for the synthesis of antimalarial drug involving Grignard reactions more particularly for the synthesis of lumefantrine. Another object of the present invention is to provide a process for the synthesis of an intermediate 2,7 dichlorofluorene in good yield and purity. Yet another object of the present invention is to provide a process for the purification and isolation of lumefantrine. Summary of the invention: The present invention discloses improved processes for the synthesis and purification of antimalarial drug lumefantrine involving Grignard reaction. The process comprises condensation of 2,7-dihloro-9H-fluorene-4oxiran with p-chloro benzaldehyde in presence of a base to yield 2,7-dichloro -9-(4-chloro benzylidine) fluorine-4-oxirane; reaction of 22,7-dichloro -9(4-chloro benzylidine) fluorine-4-oxirane with a Grignard reagent of Formula IV in suitable organic solvent and isolation of the lumefantrine of Formula I from a suitable organic solvent. Another process comprises reaction of 2,7-dihloro-9H-fluorene-4oxiran with Grignard reagent of Formula IV to obtain compound of Formula V; reaction of compound V with p-Chloro benzaldehyde in presence of base in suitable solvent to yield lumefantrine of Formula I. 4 Detailed description of the invention 5 The present invention describes an improved process for the synthesis of an antimalarial drug more particularly lumefantrine as shown in Scheme II. In one aspect the present invention describes synthesis of compound of the formula II from fluorene which comprises the following steps a) fluorene is first reacted with N-chlorosuccinimide in presence of Hydrochloric acid using a suitable organic solvent, preferably acetonitrile to get 2,7,dichloro fluorene, the product was optionally crystallized from acetonitrile, b) this product was further reacted with chloroacetyl chloride in presence of aluminum chloride using a suitable organic solvent like dichloromethane, ethylene dichloride etc, preferably methylene chloride to give 2,7-dichloro fluorene-4-chloro ethanone, and c) this was further reacted with sodium borohydride using ethanol as a solvent to afford the compound of formula II. In another aspect the present invention provides a new process for the synthesis of compound of formula I which comprises reacting compound of formula II with p-chloro benzaldehyde in presence of a base like sodium hydroxide potassium hydroxide, potassium carbonate, sodium carbonate etc. preferably potassium carbonate using a suitable organic solvent like C1-C4 alcohols, acetonitrile, dimethyl formamide, etc. preferably dimethyl formamide at a temperature ranging from ambient to reflux temperature resulting in compound of formula III. The compound of formula III was reacted with a Grignard reagent of the formula IV using a suitable organic solvent preferably tetrahydrofuran at temperature ranging from -5 to ambient temperature preferably at 0 to 5°C to give compound of formula I. In yet another aspect the compound of formula I was isolated using a suitable organic solvent like acetonitrile, C1 to C4 alcohol, diisopropyl ether, dichloromethane, hexane, dimethylformamide, water or mixtures thereof preferably acetonitrile.methanol mixture more preferably acetonitrile. Compound of formula I was dissolved in a suitable solvent preferably toluene and precipitated by adding an antisolvent like methanol, acetonitrile. Lumefantrine was also purified by just refluxing the slurry of crude product in a suitable solvent preferably acetonitrile or mixture of the above mentioned solvent and filtering the product at ambient temperature. Lumefantrine with HPLC purity of about 99.8% was achieved using the isolation method of the present invention. 6 The Grignard reagent of the Formula IV was prepared by first reacting ethyl bromide with magnesium turning in dry solvent like tetrahydrofuran at temperature ranging from ambient to reflux, preferably at reflux, further dibutyl amine is added to the reaction mass and stirred at ambient temperature to give the Grignard reagent of formula IV. In yet another aspect the present invention provides another new process for the synthesis of compound of formula I which comprises first reacting compound of formula II with Grignard reagent IV using tetrahydrofuran as a solvent at temperature preferably between 0-5°C. to give compound of formula (V) which was further reacted with p-chloro benzaldehyde in presence of a base preferably potassium carbonate and using dimethyl formamide as a solvent at temperature ranging from ambient to 100°C preferably at 40 to 50°C to give compound of formula I, which was isolated from suitable organic solvent. The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Examples Example 1 Fluorene (50 gms) was stirred with acetonitrile (300 ml) at room temperature. N-chloro succinimide (96 gms) was added to the above mixture and was cooled to 10-15°C. Further cooled the reaction mass to 10-15°C. Cone. HC1 (75 ml) was added slowly to the reaction mass maintaining temperature below 30°C. The reaction mass was stirred at ambient temperature for about 24 hrs. Reaction mass was then chilled to 0-5°C. The solids were filtered and washed with cold acetonitrile (150 ml) and dried under vacuum at 60°C for 4-5 hrs. to give 2,7 dichloro fluorene (50 gms). Example 2 Aluminum chloride (110 gms) was suspended in dichloromethane (250 ml ), and the reaction mass was chilled to 0-5°C, chloro acetyl chloride (96 gms) was added dropwise 7 maintaining the temperature between 0-5 °C. The reaction mass was further stirred at 0-5°C for 30 min., 2,7, dichlorofluorene dissolved in dichloromethane (150 ml) was charged to the reaction mass slowly maintaining the temperature between 0-5°C. The reaction mass was stirred for about 3 hrs. at 0-5°C . After completion of reaction, the reaction mass was quenched in chilled water (1000 ml) containing 50 ml HC1 and stirred for 2 hrs. at ambient temp. Organic layer was separated and aqueous layer was extracted with dichloromethane (100 ml). Combined organic layer was washed with water followed by saturated sodium bicarbonate till neutral and finally washed with water. The organic layer was dried over sodium sulphate and concentrated; hexane (200 ml) was charged to the residue and stirred for about 1 hr. The resulting solid was filtered, washed with hexane and dried under vacuum at 60°C, resulting in 45 gms of 2,7-dichloro fluorene-4-chloro ethanone. Example 3 2,7-dichloro fluorene-4-chloro ethanone (50 gms) was suspended in denatured spirit (500 ml). Sodium borohydride (50 gms) was added in small portions to the above suspension maintaining temperature below 30°C. After complete addition, the reaction mass was stirred at ambient temperature for 24 hrs. The reaction mass was then cooled to 0-5°C and stirred for 30 min. The resulting solid was filtered and washed with chilled denatured spirit. The resulting wet product was stirred in water (1200 ml) at 50-55°C for 1 hr. The slurry was filtered hot and washed with water and dried under vacuum at 60° for 10 hrs. to give 2,7-dichloro fluorene 4-oxirane (30 gms). Example 4 2,7-dichloro fluorene 4- oxirane (20 gms) was added to dimethyl formamide ( 60 ml), potassium carbonate (20 gms) and p-chloro benzaldehyde (11 gms) was added and the reaction mass was stirred at room temperature for 3-4 hrs. After completion of reaction the reaction mass was quenched in water and extracted with dichloromethane (100 ml). The organic layer was dried over sodium sulphate and concentrated to residue. The residue was dissolved in toluene (100 ml) and methanol (140 ml) was added and stirred 8 for 3-4 hrs. The resulting solid was filtered and washed with methanol and dried under vacuum at 60°C to afford 17 gms of 2,7-dichloro-9- (4-chloro benzylidene) fluorene 4-oxirane. Example 5 Magnesium turning (5 gms) was suspended in dry tetrahydrofuran (15 ml) at ambient temperature. Ethyl bromide (14.4 ml) dissolved in tetrahydrofuran (30 ml) was added dropwise to the reaction mass. After completion of addition reaction mass was heated to 60° for 1 hr and then cooled to room temperature. Dibutylamine (37 ml) dissolved in tetrahydrofuran (40ml) was added dropwise to the above reaction mass and further stirred at room temperature for 1 hr. The Grignard reagent formed was kept aside. In another reaction flask 2,7-dichloro-9-(4-chloro benzylidene) fluorene 4-oxirane(45 gms) was dissolved in tetrahydrofuran (250 ml) and chilled to 0°C . The Gignard reagent prepared earlier was added dropwise to the above reaction mass maintaining the temperature between 0-5°C and further stirred at 0°C for additional 2 hrs. The reaction mass was then quenched into 5% chilled ammonium chloride solution (1.5 ltr) under stirring. The aqueous layer was extracted with ethyl acetate. Ethyl acetate layer was dried over sodium sulphate and concentrated to residue. The residue was dissolved in hexane and the insoluble impurity was filtered. The hexane layer was concentrated to residue, the residue was stirred in a mixture of acetonitrile: methanol (1:1) (300 ml) and stirred for 8 hr. the resulting solid was filtered and recrystallised from acetonitrile and dried under vacuum at 60°C to give 2-dibutylamino-l-[2,7-dichloro-9-(4-chlorobenzylidene)-9 H-fluoren-4-yl]-ethanol (40 gms, 99.8% HPLC purity). 9 We Claim 1. A process for the synthesis of lumefantrine of Formula (I) which comprises condensing 2,7-dichloro-9, -H-fluoren-4-oxiran of formula(II) with p-chloro benzahdehyde in a suitable organic solvent in presence of a base to yield a compound of formula (III); reacting the compound of formula (III) with a Gignard reagent of formula (IV) in suitable organic solvent and isolating compound of formula(I) from a suitable organic solvent. 10 2. A process according to claim-1 wherein said Gignard reagent (IV) is prepared by reacting alkyl magnesium bromide with dibutyl amine. 3. A process according to claim-1 wherein said solvent used in the condensation of compound (II) with p-chorobenzaldehyde is dimethylforamamide using potassium carbonate as a base. 4. A process according to claim-1 wherein said solvent used for the reaction of compound (III) with Gignard reagent (IV) is tetrahydrofuran. 5. A process according to claim-1 wherein said solvent used for isolation of lumefantrine is selected from acetonitrile, C1 to C4 alcohol, dichlormethane, hexane, dimethyl formamide, toluene, tetrahydrofuran, diisopropyl ether or or mixtures thereof. 6. A process for the synthesis of lumefantrine of Formula (I) which comprises reacting 2,7-dichloro-9H-fluoren-4-oxiran of formula(II) ci (ID with Gignard reagent of formula (IV) in a suitable organic solvent to yield a compound of formula (V); 11 reacting the compound of formula (V) with p-chloro benzaldehyde in suitable organic solvent and isolating compound of formula(I) from a suitable organic solvent. 7. The process according to claim 6 wherein said solvent used for isolation of lumefantrine is selected from acetonitrile, CI to C4 alcohol, dichloromethane, hexane, dimethyl formamide, toluene, tetrahydrofuran, diisopropyl ether or or mixtures thereof. 8. A process for the synthesis of the intermediate 2,7 dichlorofulorene, which comprises reacting fluorene with N-chlorosuccinimide and hydrochloric acid using acetonitrile as a solvent and recrystallizing the product from acetonitrile. 9. An improved process for the synthesis and purification of antimalarial drug Lume fantrine involving Gignard reaction as substantially described herein with reference to the foregoing examples 1 to 5. Dated this 25th day of April 2005 Dr. Gopakumar G. Nair Agent for the applicant

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