FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
Process for the preparation of lumefantrine
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West), Mumbai - 400 067.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of lumefantrine.
BACKGROUND OF THE INVENTION:
Lumefantrine belongs to the class of antimalarial agents and is reported to be originally synthesized in the 1970's by the Academy of Military Medical Sciences, China. Lumefantrine is chemically, (Z)-2,7-dichloro-9-[(4-chlorophenyI)methylene]- alpha-[(dibutylamino)methyl]]-9H-fluorene-4-methanol having the structural Formula I.

Coartem is a fixed dose combination of two active ingredients, artemether, a sesquiterpene lactone derivative of a naturally occurring substance, artemisinin, and lumefantrine, a synthetic racemic fluorene derivative, as indicated in artemisinin-based combination therapy (ACT) used to treat malaria including the stand by-emerging treatment of adults and children with infections due to Plasmodium falciparum or mixed infections including Plasmodium falciparum -the deadliest form of the disease. The combination has gametocytocidal action.
Plasmodium falciparum and Plasmodium vivax are the two dominant species with relative frequency of 60% and 40%, respectively. However, this proportion varies from place to place and from season to season. In malaria epidemic situations, Plasmodium falciparum is the dominant parasite species and almost all malaria deaths happen due to infections by this species. Moreover, the biological diversity of Plasmodium falciparum, its ability to develop resistance to a number of anti-malarial drugs has been a major challenge in malaria chemotherapy.


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Chinese Patent 1029680C discloses a five-step process for the preparation of lumefantrine. These five steps includes a) Chlorination of fluorene to form 2,7-dichlorofluorene of formula II; b) reaction with Chloroacetyl chloride to form ketone compound of formula III; c) formation of oxirane intermediate of formula IV; d) reaction with dibutyl amine to form amino alcohol of formula V and e) reaction with p-chlorobenzaldehyde. This complete process is shown in Scheme I. However, the lumefantrine is not obtained in pure form. Also, the process is lengthy with low overall output.

(II) (III)
Step-c


(i) ci^^^^^^ci cr^^^ ci
(V) (IV)
Scheme I
Indian patent application 509/MUM/2005 suggests the modification at step d and replaces dibutyl amine with a Grignard reagent, dibutyl amine magnesium bromide. The handling of Grignard reagent makes the process cumbersome. Moreover, Grignard reaction involves dry reaction conditions where dry solvents have to be employed which is costly affair.
Indian patent application 260/MUM/2006 suggests the coupling of step c and step d with in situ formation of oxirane intermediate of formula IV. But, this process still suffers from some disadvantages such as low overall yield.
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OBJECT OF THE INVENTION:
The object of the present invention is to provide an improved process for the preparation of lumefantrine without involving Grignard reagent.
Another object of the present invention is to provide the process for the preparation of lumefantrine intermediate (VI) without isolating oxirane intermediate.
Yet another object of invention is to provide the process for the preparation of lumefantrine in solvent free conditions.
SUMMARY OF THE INVENTION:
One major aspect of invention is to provide a process for the preparation of lumefantrine comprising the steps of
a) chloroacetylation of 2,7-dichlorofluorene to yield 2-chloro-l-(2,7-dichIoro-9H-fluoren-4-yl)ethanone of Formula III
b) reductive cyclisation of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of Formula III
c) optionally isolating 2,7-dichloro fluoren-4-oxirane of Formula IV
d) condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with 4-chlorobenzaldehyde to yield 7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI
e) condensation of 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI with N-dibutylamine
f) isolation of pure lumefantrine using one or more solvents.
One particular aspect of invention is to provide a process for the preparation of lumefantrine comprising condensation of 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane with N-dibutylamine without any solvent.
Another aspect of invention is to provide a process for the preparation of lumefantrine comprising the steps of
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a) condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with N-dibutylamine to yield 2-dibutylamino-1 -(2,7-dichloro-9H-fluoren-4-yl)ethanol (Formula V)
b) optionally isolating 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol (Formula V)
c) condensation of 2-dibutylamino-l -(2,7-dichloro-9H-fluoren-4-yl)ethanol (Formula V) with 4-chlorobenzaldehyde
d) isolation of pure lumefantrine using one or more solvents.
Detailed description of the invention:
According to one particular aspect of the invention, there is provided a process for the preparation of lumefantrine comprising the steps of
a) chloroacetylation of 2,7-dichlorofluorene to yield 2-chIoro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of Formula III
b) reductive cyclisation of 2-chIoro-l-(2,7-dichIoro-9H-fluoren-4-yI)ethanone of Formula III
c) optionally isolating 2,7-dichloro fluoren-4-oxirane of Formula IV
d) condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with 4-chlorobenzaldehyde to yield 7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI
e) condensation of 2,7-dichloro-9-(4-chIorobenzylidene)fluorene-4-oxirane of Formula VI with N-dibutylamine
f) isolation of pure lumefantrine using one or more solvents.
In one embodiment, chloroacetylation of 2,7-dichlorofluorene is carried out using chloroacetyl chloride in dichloromethane, in presence of aluminium chloride.
In another embodiment, reduction of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yI)ethanone of Formula III is carried out using metallic borohydrides selected from sodium borohydride or potassium borohydride preferably, sodium borohydride in alcoholic
S

solvent. The alcoholic solvent may be CI to C8 in length preferably, methanol or ethanol or mixture thereof.

(i) Scheme II
In yet another embodiment, reduction of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of Formula III is carried out using potassium borohydride in ethanol and the resulting reaction mixture is then treated with alcoholic alkali at about 30 °C for upto 4 hours, to yield 2,7-dichloro fluoren-4-oxirane of Formula IV. In another embodiment, reduction of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone of Formula III is carried out using sodium borohydride in methanol and the resulting reaction mixture is then treated simultaneously with alcoholic alkali and 4-chlorobenzaldehyde at about 30 °C for upto 4 hours, to yield 7-dichloro-9-(4-chlorobenzylidene)fIuorene-4-oxirane of Formula
C

VI. The said alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate preferably sodium hydroxide.
In another embodiment, condensation of 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI with N-dibutylamine is carried out in solvent-tree conditions keeping the temperature at 30 °C to 160 °C to yield crude lumefantrine. This reaction is performed preferably, at a temperature about 100 °C to about 150 °C. The mole ratio of N-dibutylamine to 2,7-dichIoro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI is about 1 to 8, preferably 1.1 to 3. In yet another embodiment, the crude lumefantrine is purified using one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl methyl ketone, acetonitrile, ethyl acetate, toluene, hexane, heptane or mixtures thereof.
Another aspect of invention is to provide a process for the preparation of lumefantrine comprising the steps of
a) condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with N-dibutylamine to yield 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4~yl)-ethanoI of Formula V
b) optionally isolating 2-dibutylamino-l-{2,7-dichJoro-9H-fIuoren-4-yl)-ethanol of Formula V
c) condensation of 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanol of Formula V with 4-chlorobenzaldehyde
d) isolation of pure lumefantrine using one or more solvents.
In another embodiment, condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with N-dibutylamine is carried out in solvent-free conditions keeping the temperature at 30 °C to 160 °C for upto 3 hours to yield 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yI)-ethanoi. This reaction is performed preferably, at a temperature about 100 °C to about 150 °C. The mole ratio of N-dibutylamine to 2,7-dichloro fluoren-4-oxirane of Formula IV is about 1 to 8, preferably 1.1 to 3.


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In yet another embodiment, condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV with N-dibutylamine is carried out in solvent-free conditions keeping the temperature at 120 to 160 °C for upto 3 hours, followed by condensation with 4-chlorobenzaldehyde in presence of alcoholic alkali at about 40 °C for upto 14 hours.
The following examples illustrate the invention without however implying a limitation.
The starting material 2,7-dichlorofluorene of Formula II was prepared according to the literature procedure (Synthesis; 1994; 1181).
Example 1
Preparation of 2-chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone (Formula III) Aluminium chloride and dichloromethane (200 ml) was cooled to -5 to 0 °C, next chloroacetyl chloride (59.38 g) was added at -5 to 0 °C. A solution of 2,7-dichlorofluorene (100 g) dissolved in dichloromethane (600 ml) was added. After 3-6 hrs the deep-red reaction mixture was transferred to 15% aqueous hydrochloric acid (850 ml). After phase separation, the organic phase was washed twice with water. Dichloromethane was distilled off and ethanol (200 ml) was added. The crystallized product was isolated by filtration to give 120 g of pure 2-Chloro-l-(2,7-dichloro-9H-fluoren-4-y l)ethanone.
Example 2
2,7-dichloro fluoren-4-oxirane (Formula IV)
2-Chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone (50 g) was suspended in ethanol (125 ml) and cooled to 5-10 °C. Now sodium borohydride (2 g) was added in parts over a period of 1 hr maintaining the temperature below 10 °C. The reaction mass was stirred at 10 °C for 2 hr. Methanolic sodium hydroxide (50 ml, 8 % w/v) was added to the reaction mixture dropwise over a period of 30 min. The reaction mixture was maintained at 30 °C for 4 hrs. The resulting solid was filtered and washed with water and methanol. The solid obtained was dried under vacuum to give 2,7-dichloro fluoren-4-oxirane (40 g).
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Example 3
2,7-dichloro-9-(4 chlorobenzylidene)fluorene-4-oxirane (Formula VI)
2,7-Dichloro fluoren-4-oxirane (50 g) and sodium hydroxide (17.3 g) were taken in
methanol (250 ml), 4-chlorobenzaIdehyde (26.6 g) in methanol (50 ml) was added to the
reaction mixture dropwise over 30 min. The reaction mixture was maintained at room
temperature for 4 hr. The resulting solid was filtered and washed with water and
methanol. The solid obtained was dried under vacuum to give 2,7-dichloro-9-(4
chlorobenzylidene)fluorene-4-oxirane (63 g).
Example 4
2,7-dichloro-9-(4-chlorobenzyldene)fluorene-4-oxirane (Formula VI) 2-Chloro-l-(2,7-dichloro-9H-fluoren-4-yl)ethanone (50 g) was suspended in methanol (125 ml) and cooled to 5-10 °C. Now sodium borohydride (2 g) was added in parts over a period of 1 hr maintaining the temperature below 10 °C. The reaction mass was stirred at 10 °C for 2 hr. Methanolic sodium hydroxide (50 ml, 8 % w/v) was added to the reaction mixture dropwise over a period of 30 min. The reaction mixture was maintained at room temperature for 4 hr. Methanolic sodium hydroxide (100 ml, 15 % w/v) and a solution of 4-chlorobenzaldehyde (22.6 g) in methanol (50 ml) were simultaneously added to the reaction mixture over a period of 30 min. The reaction mixture was maintained at 30 °C for 4 hrs. The resulting solid was filtered and washed with water and methanol. The solid obtained was dried under vacuum to give 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane (57.7 g).
Example 5
Preparation of lumefantrine (Formula I)
A mixture of 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane (50 g) and N-
dibutylamine (48.5 g) was heated at 120-130 °C. The reaction was monitored by thin
layer chromatography. After completion of reaction, excess of N-dibutylamine was
distilled off under vacuum at 90 °C and n-heptane (250 ml) was added. The reaction
mixture was maintained at 95 °C for 1 hr and cooled to 5 °C. The product was filtered
and further crystallized with acetone (200 ml) to give pure lumefantrine (26gm).
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Example 6
Preparation of lumefantrine (Formula I)
A mixture of 2,7-dichloro-9-(4-chlorobenzylidene)flu0rene_4_oxirane (50g) and N-
dibutylamine (48.5 g) was heated at 120-130 °C for aboutt 3 hours. After completion of
reaction, excess of N-dibutylamine was distilled off under vacuum at 90 °C and
methanolic sodium hydroxide (700 mL, 1 %w/v) was The mixture was stirred at
about 65 °C for 8 hours. The solid was filtered and crystallized from acetone (200 mL) to
give pure lumefentrine (58.2 g).
Example 7
Preparation of 2-dibutylamino-l-(2,7-dichloro-9H-fluoren_4_yl)_ethanol (Formula V) A mixture of 2,7-dichloro fluoren-4-oxirane (50 g)and N-dibutylamine (70 g) was heated at 120-130 °C for about 3 hours. After completion of reaction, excess of N-dibutylamine was distilled off under vacuum at 90 °C and ethanol (100 mL) was added, ffie mixture was reifiixed'tor an hour and* cooled'to oC. The product was allowed to crystallize for 2 hours. The product was filtered and driedd under vacuum to give 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanol (51.3 g).Example 8
A mixture of 2,7-dichloro fluoren-4-oxirane (50 g) and N-dibutylamine (70 g) was heated at 120-130 °C for about 3 hours. After complethion of reaction, excess of N-dibutylamine was distilled off under vacuum at 90 °C and me hanol (500 mL) was added. Then methanolic sodium hydroxide (150 mL, 8 %w/v) sand 4-chlorobenzyladehyde (18.2 g) in methanol (40 mL) were added simultaneously with stirring over a period of one hour at about 40 °C. The mixture was refluxed for 8 hours The solid was filtered and crystallized from acetone to give lumefantrine (70 g).
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WE CLAIM:
1. A process for the preparation of lumefantrine of Formula I
HO.

(I) comprising the steps of a) chloroacetylation of 2,7-dichlorofluorene to yield a compound of Formula III;
0,

b) reductive cyclisation of the compound of Formula III;
c) optionally isolating 2,7-dichloro fluoren-4-oxirane of Formula IV;
O-

d) condensation of the compound of Formula IV with 4-chlorobenzaldehyde to yield a compound of Formula VI;
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condensation of the compound of Formula VI with N-dibutylamine in absence of additional solvent
f) isolation of pure lumefantrine using one or more organic solvents.
2. A process for the preparation of lumefantrine of Formula I
HO,

(I)
comprising the condensation of 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI
O-

with N-dibutylamine, and isolation of pure lumefantrine using one or more organic solvents.
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3. A process for the preparation of lumefantrine of Formula I
HO.

(I) comprising the steps of
a) condensation of 2,7-dichloro fluoren-4-oxirane of Formula IV
0

with N-dibutylamine
b) optionally isolating 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanoI of Formula V

c) condensation of 2-dibutylamino-1 -(2,7-dichloro-9H-fluoren-4-yI)-ethanol of Formula V with 4-chlorobenzaldehyde
d) isolation of pure lumefantrine using one or more solvents.
4. The process claimed in claim 1, 2 and 3, wherein the reaction of N-dibutylamine is carried out in solvent-free conditions.
5. The process claimed in claim 1, 2 and 3, wherein the reaction of N-dibutylamine is carried out at a temperature range of about 30 °C to about 160 °C.
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6. According to claim 5, the temperature is about 100 °C to about 150 °C.
7. According to claim 1 and 2, the mole ratio of N-dibutylamine to 2,7-dichIoro-9-(4-chlorobenzylidene)fluorene-4-oxirane of Formula VI is about 1 to 8.
8. According to claim 3, the mole ratio of N-dibutylamine to 2,7-dichloro fluoren-4-oxirane of Formula IV is about 1 to 8.
9. According to claim 5 and 6, the mole ratio is about 1.1 to 3.
10. According to claim 1 and 2, the solvent for the isolation of pure lumefantrine is
selected from methanol, ethanol, isopropanol, acetone, ethyl methyl ketone, acetonitrile,
ethyl acetate, toluene, hexane, heptane or mixtures thereof.
(Dr.Eswaran K Iyer) GM- Intellectual Property For Ajanta Pharma Limited
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