FORM-2


THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10, rule 13]
Improved One Pot Process for the Synthesis of Lumefantrine
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956

The following specification particularly describes the invention



TITLE
Improved One Pot Process for the Synthesis of Lumefantrine
FIELD OF THE INVENTION:
The present invention relates to an efficient one pot process for the synthesis of (Z)-2-(dibutyiamino)-1 -(2, 7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl) ethanol of formula-I, commonly known as lumefantrine (formerly known as Benflumetol). More particularly, the present invention provides an improved one pot process for the selective synthesis of Z-isomer of lumefantrine from 2,7-dichlorofluorene-4-chloro ethanone in an inert atmosphere.

Formula I
The present invention further relates to an improved process for the synthesis of polymorphic Form-I of lumefantrine by one step synthesis of 2-(dibutyIamino)-l-(2,7-dichioro-9/f-fluoren-4-yl)ethanol from 2,7-dichlorofluorene-4-chloro ethanone in an inert atmosphere.
BACKGROUND OF THE INVENTION:
(Z)-2-(Dibutylamino)-l-(2,7-dichloro-9-(4-chlorobenzylidene)-9//-fluoren-4-yl)ethanoI of formula I, commonly known as Lumefantrine (formerly known as
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Benflumetol), belongs to the class of antimalarial agents. Lumefantrine is useful for the treatment of uncomplicated, severe complicated and multi-drug resistant malaria.

Formula I
Lumefantrine, 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.
Chinese patent CN1042535 discloses the synthesis of lumefantrine as shown in Scheme I. The synthesis involves preparation of 2,7-dichlorofluorene-4-chloro ethanone which is reduced to 2-(2,7-dichloro-9#-fluoren-4-yl)oxirane using potassium borohydride as a reducing agent. The oxirane intermediate is then treated with dibutylamine and the resulting product is reacted with p-chlorobenzaldehyde in ethanol in presence of sodium hydroxide to give lumefantrine of formula I.



CN1865227 describes the preparation of lumefantrine comprises the preparation of keto product which is reduced with sodium borohydride to afford 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane. The oxirane intermediate is then treated with a Grignard reagent to give dibutylamino product which is further reacted with 4-chlorobenzaldehyde to give lumefantine of formula I. The patent also describes the alternate process, in which 2,7-dichloro-9-(4-chlorobenzyIidene)fluorene-4-oxirane is first reacted with 4-chlorobenzaldehyde using DMF as a solvent to give compound of formula 3, which is then treated with Grignard reagent to give lumefantrine of formula I.




Scheme II
WO2006117616 provides the preparation of polymorphic Form-I of lumefantrine wherein lumefantine is prepared by reacting 2-(dibutylamino)-l-(2,7-dichloro-9#-fluoren-4-yl)ethanol with p-chlorobenzaldehyde in large excess of ethanol in presence of sodium hydroxide for 60 hours (Scheme III). Lumefantrine thus



obtained is then converted to its polymorphic form by obtaining and cooling its solution in one or more organic solvents at 25 °C.

Organic Process Research and Development, 2007, 11, 341-345 describes an improved process.for manufacturing of lumefantrine. The process involves (Scheme IV) the preparation of keto product of formula 3 which is converted to 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanol of formula 5 in one pot. One pot conversion comprises the reduction of keto product with sodium borohydride and in situ reaction with dibutylamine to give 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanol (5). The compound of formula 5 is then treated with p-chlorobenzaldehyde in presence of sodium hydroxide in ethanol to get an approximately 1:1 mixture of E and Z - isomers of lumefantrine, which is then subjected to isomerization and crystallization to obtain the Z-isomer of lumefantrine.
The process involves rapid heating and cooling. Purification of crude Z-isomer is carried out using another solvent. It is also noted that a little prolonged period of heating leads to an impurity generation. In our observation the process is very sensitive and needs utmost monitoring and control.
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Scheme IV
The prior art mentioned herein thus suffers from several drawbacks. The processes involve several steps of synthesis with isolation of each intermediate. Also involve tedious workup procedures and large volume of solvents. Thus, make the processes tedious and with longer reaction time. Some of the processes involve Grignard reaction, which causes the process more tedious and time consuming.
None of the prior art discloses the preparation of lumefantrine in one pot with use of single solvent. Also none of the patented processes mention the purity of the Z-isomer and in most of the processes the cycle time is as lengthy as 60 hours.
Even though the Organic Process Research and Development article claims an improved manufacturing process of lumefantrine by in situ conversion of keto product to dibutylamine derivative the process suffers from some major drawbacks. The said process is carried out at high temperature. The process requires large volume of solvent, as large as 15 times that of input, rapid heating from 23° C to 70°



C within an hour and immediate cooling up to 38° C makes the process complicated on large scale. Also the process involves tedious work up procedure and several hours of agitation to obtain complete crystallization of the product. Thus, the process is very complicated and incompatible on the large scale. Also we were unable to get consistent results with the said process.
The inventors of the present invention surprisingly found out an efficient process for the synthesis of lumefantrine of formula I. The process of the present invention is a one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I from 2,7-dichlorofluorene~4-chloro-ethanone in an inert atmosphere, which is absolutely free of any oxygen. One pot process of the present invention avoids the isolation of the intermediates such as 2,7-dichloro-9-(4-chlorobenzylidene)fluorene-4-oxirane and 2-dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)-ethanoI. The process is performed at lower temperature and in shorter period of time using a single solvent. The process of the present invention uses much reduced solvent volumes than prior art processes. Also it further uses the same solvent for the purification of the final product.
The inventors of the present invention also observed that since the present process is carried out in inert atmospheric conditions, which is absolutely free of any oxygen it avoids any contact with oxygen throughout the reaction. Hence, the process of the present invention reduces oxidative impurities and cut down oxidative stress on the reactant. This makes the process more imperative to achieve high purity of lumefantrine.
Thus, one pot process of the present invention for the selective synthesis of Z-isomer of lumefantrine of formula I overcomes the drawbacks of prior art such as longer reaction time, use of different solvents for different stages, use of large volumes of solvents, high temperature conditions and tedious work up procedures. This makes the process more imperative to achieve high yield and purity in a shorter cycle time. Furthermore dibutylamine used is recovered by acid-base treatment of the filtrate.
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Hence, one pot process of the present invention for the selective synthesis of Z-isomer of lumefantrine is more efficient, with very less or oxidative impurity free, robust, economical and environment friendly.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved and efficient one pot process for the selective synthesis of Z -isomer of lumefantrine of formula I.
Another object of the present invention is to provide an improved one pot process for the selective synthesis of substantially pure Z-isomer of lumefantrine of formula I with high yield.
Another object of the present invention is to provide an improved one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I in overall shorter reaction time.
Another object of the present invention is to provide an improved one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I using a single solvent.
Another object of the present invention is to reduce oxidative impurities and to cut down oxidative stress on the reactant by using inert atmosphere in process conditions.
Yet another object of the present invention is to provide an environmental friendly and economical process for the selective synthesis of Z-isomer of lumefantrine of formula I.
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Another object of the present invention is to provide a process for the selective synthesis of Z-isomer of lumefantrine of formula I, which is easy to operate at commercial scale.
Yet another object of the present invention is to provide an improved process for the synthesis of polymorphic Form-I of lumefantrine of formula I.
SUMMARY OF THE INVENTION
The present invention provides an improved and efficient one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I from 2,7-dichlorofluorene-4-chioro ethanone of formula II in an inert atmosphere (Scheme V)

comprising,
1 reacting 2,7-dichlorofluorene-4-chloro ethanone of formula II with reducing
agent in an organic solvent such as alcohol at 0-25 °C for 2-6 hr. followed by
gradually heating the reaction mixture to 50-60 °C
2 adding dibutylamine to the above reaction mixture optionally in presence of
a base and heating the reaction mixture to 65-140 °C for 6-10 hr.
3 adding 4-chlorobenzaldehyde and a base to the above reaction mixture at
room temperature and stirring for 1-2 hr. followed by gradually heating the
reaction mixture to 25-70 °C for 4-6 hr.
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4 cooling the reaction mixture at 0-5 °C for 1-2 hr, to obtain Z-isomer of lumefantrine of formula I.

The present invention further provides an improved process for the synthesis of polymorphic Form-1 of lumefantrine in an inert atmosphere comprising,
a. preparing 2-(dibutylamino)-1 -(2,7-dichloro-9//-fluoren-4-yl)ethanol of formula IV from 2,7-dichlorofluorene-4-chloro ethanone of formula II in one step.


b. reacting compound of formula IV, obtained by one step synthesis in step a
with 4-chlorobenzaldehyde and a base at room temperature for 1-2 hr.
followed by gradually heating the reaction mixture to 25-70 °C for 4-6 hr.
c. cooling the reaction mixture at 0-5 °C for 1-2 hr. to obtain Z-isomer of
lumefantrine of formula I.
d. crystallizing the Z-isomer of lumefantrine of formula 1, obtained in step c
using alcoholic solvent to obtain polymorphic Form-I of lumefantrine of
formula I.
DETAILED DESCRIPTION OF THE INVENTION
Lumefantrine has emerged as a new drug for the treatment of chloroquine resistant, pernicious malignant malaria. The present invention relates to an improved and efficient one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I, without isolation and purification of intermediates, in an inert atmosphere.
The present invention further relates to an improved process for the synthesis of polymorphic Form-1 of lumefantrine by one step synthesis of 2-(dibutylamino)-l-(2,7-dichloro-9//-fluoren-4-yl)ethanol from 2,7-dichlorofluorene-4-chloro ethanone in an inert atmosphere.
For the present invention the term "Inert atmosphere" refers to an atmospheric condition, which is absolutely free of any oxygen. It includes pure nitrogen atmosphere, argon atmosphere or helium atmosphere.
According to an aspect of the present invention there is provided an improved one pot process for the selective synthesis of Z-isomer of lumefantrine of formula I from 2,7-dichlorofluorene-4-chloro ethanone of formula II in an inert atmosphere comprising,
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1. reacting 2,7-dichlorofluorene-4-chloro ethanone of formula II

Formula II
with reducing agent in an organic solvent such as alcohol at 0-25 °C for 2-6 hr. followed by gradually heating the reaction mixture to 50-60 CC
2. adding dibutylamine to the above reaction mixture optionally in presence of a base and heating the reaction mixture to 65-140 °C for 6-10 hr.
3. adding 4-chlorobenzaldehyde and a base to the above reaction mixture at room temperature and stirring for 1-2 hr. followed by gradually heating the reaction mixture to 25-70 °C for 4-6 hr.
4. cooling the reaction mixture at 0-5 DC for 1-2 hr. to obtain Z-isomer of lumefantrine of formula I
One pot process of the present invention is as depicted in the Scheme-V below
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Scheme V
The compound of formula 11 is prepared by the well known prior art processes.
In an embodiment of the present invention compound of formula II is first reduced to compound of formula III in presence of an organic solvent such as alcohol. The reaction mixture containing compound of formula III is taken as such for the dibutylamine condensation, without isolating and purifying the compound of formula III. The reaction mixture containing compound of formula III is then reacted with dibutylamine optionally in presence of base in same solvent. After completion of reaction the reaction mixture containing compound of formula IV is treated with p-chlorobenzaldehyde in presence of base in same solvent followed by isomerisation of lumefantrine to obtain Z-isomer of lumefantrine of formula I selectively. This entire one pot process is performed in an inert atmosphere.
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Thus, one pot process of the present invention avoids the isolation and purification of the intermediates of compound of formula III and compound of formula IV. The entire process is carried out in a single solvent. The inventors of the present invention found out that the process requires much less amount of solvent than prior art process and also it requires overall short reaction time and obtain lumefantrine in high yield and purity.
In another embodiment, the process of the present invention is carried out in an inert atmosphere that is absolutely free of any oxygen. Inert atmosphere used herein can be pure nitrogen, argon or helium, preferably argon.
The process of the present invention avoids the formation of oxidative impurities and cut down oxidative stress on the reactant since the process is carried out in inert an atmospheric condition that is absolutely free of any oxygen.
In another embodiment of the present invention the one pot process of the present invention is carried out in a single solvent such as alcoholic solvent.
The alcoholic solvent used in the whole reaction is selected form aliphatic alcohols such as methanol, ethanol, 1-propanol, 2-propanol or n-butanol, preferably n-butanol or 1-propanol.
The amount of organic solvent used in the whole reaction ranges from 3-10 volumes, preferably 4-6 volumes.
Reducing agent used is selected from alkali and alkaline earth metal borohydrides such as sodium borohydride, potassium borohydride or sodium cyanoborohydride, preferably sodium borohydride or potassium borohydride.
The amount of compound of formula II and reducing agent used are in the ratio of 1:0.25 to 1:1, preferably in the ratio 1:0,5.
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The reduction reaction is carried out at temperature 0 °C to 25 °C, preferably at temperature 0 DC to 5 °C for 2-6 hr, preferably for 2-4 hr.
The base used for step-2 reaction is organic or inorganic base. Organic base is selected form trialkylamine such as triethylamine, pyridine, piperidine, DBU or DMAP and inorganic base is selected form alkali and alkaline earth metal carbonates such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate or alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, preferably the base used for dibutylamine condensation is inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate, or potassium bicarbonate.
The step-2 reaction is carried out at temperature 65 °C to 140 °C, preferably at temperature 75 °C to 100 °C for 4-12 hr., preferably for 6-10 hr.
When dibutylamine condensation reaction of step-2 is carried out using a base, amount of compound of formula III and dibutylamine are used in the ratio of 1:1 to 1:3, preferably in the ratio of 1:1 to 1:1.1 and the amount of base used is 0.5 to 3.0 moles, preferably 1.2 to 1.5 moles.
In absence of base the amount of compound of formula III and dibutylamine are used in the ratio of 1:1 to 1:3, preferably in the ratio of 1:2 to 1:2.5.
The base used for step-3 reaction is inorganic or organic base. Organic base is selected form trialkylamine such triethylamine, pyridine, piperidine, DBU or DMAP. Inorganic base is selected from alkali and alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide or lithium hydroxide, or alkali and alkaline earth metal carbonate or bicarbonates, preferably base used is alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.
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The amount of compound of formula-IV and p-chlorobenzaldehyde used are in the ratio of 1:1 to 1:1.3, preferably in the ratio of 1:1 to 1:1.15,
The amount of compound of formula-IV and base used are in the ratio of 1:0.1 to 1:2.5, preferably in the ratio of 1:1 to 1:1.2.
The condensation reaction of step-3 is carried out at temperature 10-55 °C, preferably at temperature 25-30 °C for l-4hr., preferably for 2-3 hr.
Isomerisation reaction of lumefantine is carried out at temperature 25-70 °C, preferably at temperature 40-60 °C for 4-10 hr., preferably for 4-6 hr.
In yet another embodiment of the present invention crude lumefantrine of formula I is purified using a single organic solvent such as alcohol or optionally with mixture of two or more organic solvents to obtain substantially pure Z-isomer of lumefantrine of formula I.
The Z-isomer of lumefantrine obtained after purification has HPLC purity > 99.5%
Alcoholic solvent used for purifying crude lumefantrine is selected form methanol, ethanol, propanol, butanol, 1-propanol etc.
The organic solvents used in combination with alcohol are selected from esters like ethyl acetate, methyl acetate, butyl acetate or propyl acetate; halogenated solvents like dichioromethane, dichloroethane, dichloropropane or chloroform; aromatic solvents like, benzene, toluene, ethyl benzene, xylene etc; preferably the solvent used in combination with alcohol is ethyl acetate.
According to another aspect of the present invention there is provided an improved process for the synthesis of polymorphic Form-I of lumefantrine comprising,
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a. preparing 2-(dibutylamino)-l -(2,7-dichloro-9i/-fluoren-4-yl)ethanol of
formula IV from 2,7-dichlorofluorene-4-chloro ethanone of formula II in one
step .
b. reacting compound of formula IV, obtained by one step synthesis in step a
with 4-chlorobenzaldehyde and a base at room temperature for 1-2 hr.
followed by gradually heating the reaction mixture to 40-60 °C for 4-6 hr.
c. cooling the reaction mixture at 0-5 °C for 1-2 hr. to obtain Z-isomer of
lumefantrine of formula I.
d. crystallizing the Z-isomer of lumefantrine of formula I, obtained in step c
using alcoholic solvent to obtain polymorphic Form-I of lumefantrine.
In step-a of the process of the present invention compound of formula IV is prepared in one step by reducing compound of formula II to compound of formula III in presence of an organic solvent such as alcohol in an inert atmosphere. The reaction mixture containing compound of formula III is taken as such for the dibutylamine condensation, without isolating and purifying the compound of formula III. The reaction mixture containing compound of formula III is then reacted with dibutylamine optionally in presence of base in same solvent to obtain compound of formula IV. Compound of formula IV is then isolated and optionally purified.
Compound of formula IV is then treated with p-chlorobenzaldehyde in presence of base followed by isomerisation of lumefantrine to obtain Z-isomer of lumefantrine of formula I which is further purified using alcoholic solvent to obtain polymorphic Form-I of lumefantrine.
Reaction details of Step-a to Step- C are same as described for one pot process above.
In further embodiment of the present invention crude lumefantrine obtained in step-c is crystallized using single alcoholic solvent to obtain Polymorphic Form-I of lumefantrine.
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Alcoholic solvent is selected from methanol, ethanol, propanol, butanol or 1-propanol.
Alternatively, crystallization is also carried out using alcoholic solvent in combination with another organic solvent such as dichloromethane, ethyl acetate or toluene.
The amount of compound of formula I and single solvent used for purification ranges from 2 to 6 volumes, preferably 3 volumes.
The amount of mixed solvent ratio used for purification are in the ratio of 1:8, preferably 1.5:3.0 to 2.0:7.0 and the amount of compound of formula I and mixed solvent used ranges from 5 to 10 volumes, preferably ranges from 6 to 8 volumes.
Polymorphic Form-I of lumefantrine is confirmed by x -ray powder diffraction and DSC.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
Experimental Procedure:
Reference example-l
Synthesis of 2,7-dichlorofluorene-4-chloro ethanone of formula II
To the stirred slurry of aluminum chloride (127.6g, 0.9569 moles) in dichloromethane (255.0ml) was added chloroacetyl chloride (82.34g, 0.729 moles) at 0 to 5 °C over a period of 25-30 minutes. The solution of 2,7-dichlorofluorene (150.0g, 0.6379 moles) in dichloromethane (675.0ml) was added drop wise at 0 to 5 °C over a period of 1.0 to 1.5 hrs and maintained further for 3 to 4 hrs. After
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completion of reaction it was quenched in ice-cold water (1200.0ml). Organic layer was separated out and aqueous layer was extracted with dichloromethane. Combined organic layer was washed with water (500.0 ml), 10% aqueous sodium bicarbonate solution (375 ml), followed by water (500 ml). Dichloromethane layer was concentrated to residue under reduced pressure at 25-35 °C and degassed under high vacuum to obtain compound of formula II. Weight of the formula II = 191.6g (96.46%); HPLC purity: 90.0%; LOD = 0.27%. (Optionally the crude compound of formula II can be purified using alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol)
Reference cxample-2
Synthesis of 2,7-dichlorofluorene-4-chloro et ha none of formula II
To the stirred slurry of aluminum chloride (86.67g, 0.6469 moles) in dichloromethane (170.0ml) was added chloroacetyl chloride (55.32g, 0.4898 moles) at 0 to 5 °C over a period of 25-30 minutes. The solution of 2,7-dichlorofluorene (lOO.Og, 0.4253 moles) in dichloromethane (500.0ml) was added drop wise at 0 to 5 °C over a period of 1.0 to 1.5 hrs and maintained further for 3 to 4 hrs. After completion of reaction it was quenched in ice-cold water (800.0ml), Organic layer was separated out and aqueous layer was extracted with dichloromethane (2 x 300.0ml). Combined organic layer was washed with water (500.0 ml), 10% aqueous sodium bicarbonate solution (250 ml), followed by water (300 ml). Dichloromethane layer was concentrated to residue under reduced pressure at 25-35 °C and degassed under high vacuum. Weight of the formula II: 136g; HPLC purity: 96.73%. (Optionally the crude compound of formula II can be purified using alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol).
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Example 1
One pot process for synthesis of Z-isomer of lumefantrine
To the stirred slurry of compound of formula II (lOOg, 0.3209 moles) in n-butanol (500.0ml) was added aqueous solution of sodium borohydride (6.07g of NaBH4 in 40 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to 50-60 °C. The di-n-butylamine (41.47g, 0.3209 moles), followed by sodium bicarbonate (32.34g, 0.3850 moles) was added and reaction mass was heated to 95-100 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to room temperature and stirred for 1 -2 hrs.
To the above reaction mixture was added 4-chlorobenzaldehyde (46.5g, 0.3308 moles) followed by sodium hydroxide (17.32g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs, It was then gradually cooled to 0-5 °C and stirred for 1-2 hrs. Yellow solid was filtered out and washed with water. Weight of formula I (lumefantrine): 115.0g; HPLC purity: 99.0%; Z-Isomer: >95%.
Above crude lumefantrine (115g) was taken in n-butanol (862.5ml) and was heated to 85-90 °C to get clear solution. The clear solution was filtered at hot and was gradually cooled to room temperature. The slurry was cooled further to 0-5 °C and stirred for 1.0-1.5 hrs. Yellow crystalline solid was filtered out and dried under vacuum at 60-70 °C to obtain substantially pure Z-isomer of lumefantrine of formula L Yield of formula I: 105.0g; HPLC Purity: 99.80%.
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Example 2
One pot process for synthesis of Zrisomer of lumefantrine
To the stirred slurry of compound of formula II (lOOg, 0.3209 moles) in n-butanol (500.0ml) was added aqueous solution of sodium borohydride (6.07g of NaBRt in 40 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to 50-60 °C. The di-n-butylamine (103.69g, 0.8023 moles) was added and reaction mass was heated to 95-100 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to room temperature and stirred for 1 -2 hrs.
To the above reaction mixture was added 4-chlorobenzaldehyde (51.87g, 0.3690 moles) followed by sodium hydroxide (30.8g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs. It was then gradually cooled to 0-5 °C and stirred for 1-2 hrs. Yellow solid was filtered out, washed with water and dried under vacuum. Weight of formula I (lumefantrine): 118.0g; HPLC purity: 99.59%; 2-Isomer: >95%.
Crude Lumefantrine was purified using the methods mentioned in Example 1. Yield of pure (Z-isomer) lumefantrine: 109g; HPLC Purity: 99.83%.
Example 3
One pot process for synthesis of Z-isomer of lumefantrine
To the stirred slurry of compound of formula II (lOOg, 0.3209 moles) in ethanol (1000.0ml) was added aqueous solution of sodium borohydride (6.07g of NaBRt in 40 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to
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50-60 °C. The di-n-butylamine (43.55g, 0.3369 moles), followed by sodium bicarbonate (32.34g, 0.3850 moles) was added and reaction mass was heated to 75-85 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to room temperature and stirred for 1 -2 hrs.
To the above reaction mixture was added 4-chlorobenzaldehyde (47.3 5g, 0.3369 moles) followed by sodium hydroxide (27.72g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs. It was then gradually cooled to 0-5 °C and stirred for 1-2 hrs. Yellow solid was filtered out and washed with water. Weight of formula I (Lumefantrine): 90 g; HPLC purity: 99.0%
Crude Lumefantrine was purified using the methods mentioned in Example 1 to give Z-isomer of lumefantrine with >99.5% HPLC Purity.
Example 4
One pot process for synthesis of Z-isomer of lumefantrine
To the stirred slurry of compound of formula II (lOOg, 0.3209 moles) in methanol (500.0ml) was added aqueous solution of sodium borohydride (6.07g of NaBH4 in 40 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to 50-60 °C. The di-n-butylamine (43.55g, 0.3369 moles), followed by sodium bicarbonate (32.34g, 0.3850 moles) was added and reaction mass was heated to 65-75 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to room temperature and stirred for 1-2 hrs.
To the above slurry was added 4-chlorobenzaldehyde (47.35g, 0.3369 moles) followed by sodium hydroxide (27.72g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs. It was then
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gradually cooled to 0-5 CC and stirred for 1-2 hrs. Yellow solid was filtered out and washed with water. Weight of formula I (lumefantrine): 60.7g; HPLC purity: 74%.
Crude Lumefantrine was purified using the methods mentioned in Example 1. Example 5
Synthesis of polymorphic Form -I of Lumefantrine
To the stirred slurry of crude compound of formula II, from reference example I (190g, 0.6097 moles) in n-butanol (760.0ml) was added aqueous solution of sodium borohydride (11.53g of NaBRj in 60 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to 50-60 °C. The di-n-butylamine (86.71g, 0.6709 moles), followed by sodium bicarbonate (56.32g, 0.6705 moles) was added and reaction mass was heated to 95-100 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to 50-60 °C and washed with 5% aqueous sodium hydroxide solution, followed by brine. Organic layer was cooled to 0 to 5 °C, product was filtered out and suck dried well. Yield of formula IV: 243.0g (wet); HPLC Purity: 97.1%; LOD: 14.7%. (Optionally the crude compound of formula IV can be purified using alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol)
Above wet cake of crude compound of formula IV (243.0g) was taken in n-butanol (1050.0ml) and was added 4-chlorobenzaldehyde (88.0g, 0.6260 moles) followed by sodium hydroxide (26.0g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs. It was then gradually cooled to 0-5 °C and stirred for 1-2 hrs. Yellow solid was filtered out and washed with water. Weight of formula I (lumefantrine): 270.0g (LOD: 15%); HPLC purity: 99.41%; Z-Isomer. >95%.
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Wet cake of crude lumefantrine (270g) was taken in n-butanol (1700.0ml) and was heated to 85-90 °C to get clear solution. The clear solution was filtered at hot and was gradually cooled to room temperature. The slurry was cooled further to 0-5 °C and stirred for 1,0-1.5 hrs. Yellow crystalline solid was filtered out and dried under vacuum at 60-70 °C. Yield of formula 1 (Z-isomer): 197.0g; HPLC Purity: 99.86%.
Alternatively the crude lumefantrine may be purified using a mixture of alcohol such as n-butanol, isopropyl alcohol, ethanol or methanol with methylene dichloride, ethyl acetate or toluene at room temperature to 60 °C to give Z-isomer of lumefantrine with >99.5% HPLC Purity.
*H NMR in CDC13: 5 7.66 (d, 2H, J= 1.89 Hz, 2 x Ar-H), 7.53 (d, IH, J = 8.42 Hz, Ar-H) 7.50 (s, IH, Ar-H), 7.42 (brd s, 5H, 4 x Ar-H & C-CH-), 7.28 (dd, IH, J = 8.32 & 1.89 Hz, Ar-H), 5.30 (dd, IH, J= 10.06 & 3.23 Hz, ArCH(OH)CH2N-), 4.55 (brd, IH, -OH), 2.85 (dd, IH, J= 12.97 & 3.4 Hz, CHfOH)CH2N-), 2.72-2.63 & 2.55-2.38 (2 x m, 5H, CHfOH)CH,NfCHr)CHr). 1.54-1.32 (m, 8H, N(CH2CH2CH2CH.Vl 0.96 (t, 6H, J= 14.35 Hz, 2 x -CH3). nC NMR in CDC13: 5141.42, 139.78, 138.10, 136.28, 134.88, 134.81, 134.59, 134.05, 133.07, 132.72, 130,49, 128.98, 128.24, 127.53, 126.24, 123.81, 122.88, 120.53, 65.39, 59.82, 53.32, 28.99, 20.55, 14.04.
IR(KBr): 3400.50, 2953.02, 2929.87, 2870.08, 2839.22, 1633.71, 1589,34, 1487.12, 1442.75, 1402.25, 1269.16, 1085.92, 1070.49, 873.75, 839.03, 769.60 cm"1. HPLC Purity: 99.86%, M.P.: 128.1-129.6 °C. Polymorph data:
Lumefantrine prepared in n-butanol solvent and crystallized in single n-butanol solvent;
Lumefantrine polymorph Form-I is characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 5.24, 5.57, 11.13, 20.13, 22.37, 23.06, 23.76 and 26.91 degrees. Lumefantrine polymorph Form-I is also supported by DSC peak at 133.65 °C
Lumefantrine prepared in n-butanol solvent and crystallized in mixture of solvents 1 dichloromethane/n-butanol:
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Lumefantrine polymorph Form-I is characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 5.20, 5.54, 11.10, 14.92, 18.03, 20.12, 20.94, 21.97, 23.05, 23.75, 25.24, 25.42 and 26.91 degrees
Example 6
Synthesis of polymorphic form -I of Lumefantrine
To the stirred slurry of crude compound of formula II, from reference example II (136g) in n-butanol (520.0ml) was added aqueous solution of sodium borohydride (8.8 Ig of NaBH4 in 53 ml of water) under inert atmosphere at 0 to 5 °C over a period of 1.0-1.5 hrs. After addition, reaction mixture was stirred for 2-3 hrs at 0-5 °C. After completion of reaction, it was warmed to room temperature and gradually heated to 50-60 °C. The di-n-butylamine (134.0g, 1.034 moles) was added and reaction mass was heated to 95-100 °C and maintained for 6-10 hrs. After completion of reaction, it was cooled to 50-60 °C and washed with 5% aqueous sodium hydroxide solution, followed by brine. Organic layer was cooled to 0 to 5 °C, product was filtered out and suck dried well. Yield of formula IV: 160.0g (wet); HPLC Purity: 96.51%; LOD: 20.0%. (Optionally the crude compound of formula IV can be purified using alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol).
Above wet cake of crude compound of formula IV (160.0g) was taken in n-butanol (600.0ml) and was added 4-chIorobenzaldehyde (47.0g, 0.3343 moles) followed by sodium hydroxide (13.0g) at room temperature. Reaction mixture was stirred at room temperature for 1.0-2.0 hrs. After completion of reaction, it was heated to 40-60 °C and maintained at the same temperature for 4-6 hrs. It was then gradually cooled to 0-5 °C and stirred for 1-2 hrs. Yellow solid was filtered out, washed with water and dried under vacuum. Weight of formula I (lumefantrine): 133.0g; HPLC purity: 99.46%; Z-Isomer: >95%.
Above crude lumefantrine (128g) was taken in n-butanol (960.0ml) and was heated to 85-90 °C to get clear solution. The clear solution was filtered at hot and
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*

was gradually cooled to room temperature. The slurry was cooled further to 0-5 °C and stirred for 1.0-1.5 hrs. Yellow crystalline solid was filtered out and dried under vacuum at 60-70 °C to obtain polymorphic Form-I of lumefantrine. Yield of formula I: 121.0g; HPLC Purity: 99.9%.
Optionally crude Lumefantrine may be purified using the alternative purification methods mentioned in Example 5 to give polymorphic Form-I of lumefantrine with >99.5% HPLC Purity.