FORM-2
THE PATENTS ACT, 1970
Complete Specification
(Section &Raule 13)
Title:- An Improved process for the preparation of Lumefantrine and its intermediates thereof,
M/s. Aanjaneya Lifecare Limited Aanjaneya house, Plot No 34, Postal Colony, Chembur MUMBAI-400 071
The following specification describes the invention and the manner in which it is to be performed:-

Title:-
An improved process for the preparation of Lumefantrine and its intermediates thereof. Field of the invention:-
The present invention relates to an improved process for the preparation of Lumefantrine, and its intermediates in the synthesis of Lumefantrine. Background of the Invention:-
Lumefantrine, a molecule of formula 1, is a potential oral drug indicated in the treatment of acute, uncomplicated Plasmodium falciparum malaria in combination with Artemether of formula 2, an artemisinin derivative. Artemether has a rapid onset of action and is rapidly eliminated, whereas Lumefantrine is eliminated more slowly. Consequently, the combination rapidly clears parasites, while also preventing reappearance of parasite in the blood. In the fixed-dose combination Lumefantrine is dominant component. Keeping this in view the inventors are aimed to develop a new cost effective method for the preparation of Lumefantrine by reducing synthetic steps, altering reactant, solvent and increasing overall yield and productivity at higher purity.
The prior published document an Academy of Military Medical Sciences, China in the 1970 which teaches about synthesis of Lumefrantrine, and latter disclosed in Chinese Patent No. CN1029680C with seven step process having no good quality and with less purity and it summarized in the following scheme
Scheme 1:
Reagents and Conditions: (a)C12, AcOH, 40 0C; (b) C1CH2COC1, A1C13, CH2C12, 0 - 5
0C; (c) NaBH4, EtOH, 0 - 5 0C; (d) NaOMe, 50 - 60 0C; (e) Dibutylamine, EtOH, 78
0C, 15h; (f)p-Chlorobenzaldehyde, NaOH, EtOH; (g) Isolation of crude by
crystallization, 38 0C, 24 h; (h) Recrystallization from 2-propenol.
Prior published docuent of P.C. Fuenfschilling et al, Org. Proc. Res. Dev.; 11, 341-345,
2007.) which has modified the above process of preparing Lumefantrine by avoiding the
step preparation of 7 the reaction mechanism is as shown below,
Reagents and Conditions: (a)C12, AcOH, 35 - 40 0C, 90 0C; (b) C1CH2COC1, A1C13, CH2C12, 0 - 5 0C, H+, EtOH; (c) NaBH4, EtOH, -5 to 5 0C, dibutylamine,140 0C, OH-, EtOH; (d)p-Chlorobenzaldehyde, NaOH, EtOH, 70 0C, heptanes, 94 0C. As per the process described in Chinese patent CN1029680C Lumefantrine is prepared by chlorination of commercial fluorine with chlorine gas in the presence of acetic acid and the resultant was 2, 7-dichloro-9H-fluorine, 4, which converted in to 2-Chloro-l-( 2, 7-dichloro-9H-fluoren-4-yl)ethanone,5, through the Fu Shi reaction with chloroacetyl chloride. The compound 5 is reduced in to its chlorohydrine, 6, with sodium borohydride using ethanol as solvent. The epoxide, 7, of Chlorohydrine was prepared by using sodium methylate with 86% yield. Ring opening of epoxide to form 2-Dibutylamino-l-(2, 7-dichloro-9H-fluoren-4-yl) ethanol, 8, was performed by using excess of dibutyl amine at 78 0C for at least 15 hrs. The 2-Dibutylamino-l-{2, 7-dichloro-9-[l-(4-chlorophenyl)meth-(Z)-ylidene]-9H-fluoren-4-yl}ethanol, 1, was prepared by Knoevenagel type condensation of 8 with p-chlorobenzaldehyde.

Objects of the invention:-
Important object of the present invention is to prepare lumifrantine at high purity and high yield, by using industrially feasible cost effective, new reaction and crystallization conditions for avoiding a laborious isolation and purification steps .
Detailed description of the Invention:-
The present invention aims to manufacture cost effective industrially feasible and convenient process to get high yield, high purity containing Lumifratine. The said process comprising the following steps,
A) In first aspect of the present invention which desrcribes about a process for the
preparation of 2,7-dichloro-9H-fluorene,4, from 9H-fluorene,3, sulfuryl chloride using
as a chlorinating agent and di-chloro methane as a solvent wherein the process
comprising the steps of:
preparing a solution of 9H-fluorene in dichloromethane,
adding chlorinating agent in 1 - 1.5 hrs at 18 - 20 0C,
maintaining reaction 3 - 4 hrs at 18 - 20 0C,
separating solvent by simple distillation and or distillation at reduced pressure,
crystallization of material by solvent and
finally washing with SBC solution purified water to get more than 60% yield and more
than 99% purity.
B) another aspect of the alleged invention provides one - pot process for the preparation
of 2-Dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ehanol,8, from 2,7-Dichloro-9H-
fluorene,4, without isolation of 2-Chloro- l-(2,7-dichloro-9H-fluoren-4-yl)ehanone,5
which is a crucial steps in the alleged invention,
An efforts has been made for the synthesis of 2-Chloro- l-(2,7-dichloro-9H-fiuoren-4-
yl)ehanone,5 and used in situ to convert it into 2-Dibutylamino-l-(2,7-dichloro-9H-
fluoren-4-yl)ehanol,8, wherein the process includes the steps of:
preparing a solution of chloroacetyl chloride in dichloromethane in the presence of
A1C13,
preparing a solution of 2,7-Dichloro-9H-fluorene in dichloromethane,
adding the solution of step b into step a at - 5 to 0 0C, in 45 minutes,
agitating mass of step c, until reaction complies, (3-4 hrs) at - 5 to 0 0C,
quenching the mass of step d into already prepared ice, water and HC1 mixture after that
layer separation, extraction of aqueous layer washing and dehydration of organic layer
performed,
concentrating the mass under reduced pressure at30-350C and the resultant is 5 used in
situ,
preparing solution of above mass in different alcoholic solvents or in mixture thereof,
most preferably methanol and ethanol followed by lot wise addition of sodium at - 5 to 0
0C, in 45 minutes,
agitating mass of step g, until reaction complies,(l - 2 hrs) at - 5 to 0 0C,
Adding dibutyl amine at 25 - 30 0C and distilled off solvent at atmospheric pressure
within 1 hr,
Heating the mass to 145 0C and agitating 3 - 4 hrs at the same temperature.

Cooling it to 90 0C and quenching with 10% aqueous caustic solution followed by cooling to RT layer separation,
Washing the organic layer with salt solution and concentrating it under reduced pressure at 75 0C,
adding alcoholic solvents, most preferably methanol and ethanol, or mixture thereof in the above mass and cooling to 0 0C and
agitating the above mass for 1 hr filter the solid and wash solvent used in step in to get more than 68% yield and more than 98 % purity.
C) Another aspect of the present invention provides the preparative method of 2-
Dibutylamino-l-{2, 7-dichloro-9-[l-(4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-
yl]ethanol, 1 , from 2-Dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ehanol,8. As per
existing process E/Z - isomers 9 and 1 are isolated by the Knoevenagel type of
condensation of p-Chlorobenzaldehyde with 8. Though the desired Z - isomer 1 isolated
by taking advantage of the rapid equilibrium between the two isomers but the inventors
highly aimed to explore new process condition to overcome the aforesaid inconvenience
and for that the process includes the step of:
a) preparing basic solution of 2-Dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ehanol,8 with the help of NaOH in alcoholic solvents or in mixture thereof, most preferably methanol and ethanol at RT,
b) preparing solution of p- chlorobenzaldehyde in alcoholic solvents or in mixture thereof, most preferably as used in step a, at RT,
c) adding solution of step b into solution of step a at RT,
d) increasing the temperature of reaction mass to 70 0C v/ithin 1 hr followed by cooling to 38 0C within 1 hr,(this is the key step to get desired Z - isomer,l,)
e) agitating the mass until reaction complies,4 - 6 hrs, strictly at 38 0C,
f) cooling the reaction mixture to 25 - 30 0C, filter and wash with solvent, same as used in step a and b, to get the crude 2-Dibutylamino-l-{2, 7-dichloro-9-[l-(4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-yl}ethanol, 1 .
D) Another aspect of invention provides a new method for purification and
recrystallization of Lumefantrine or 2-Dibutylaminol-{2, 7-dichloro-9-[l-(4-
chlorophenyl) meth-(Z)-ylidene]-9H-fiuoren-4-yl}ethanol 1, and process herein
comprises the steps of:
a) heating the mixture of crude and acetone up to reflux and agitating for 2 hrs,
b) separating undesired impurities by filtration at 60 0C followed by cooling the filtrate to 20-25 0C,
c) filtering and washing the product with acetone to get more that 65% yield and more than 99.77% purity.
Reagents and Conditions: (a) S02C12, CH2C12, 20 - 30 0C; (b) C1CH2COC1, A1C13, CH2C12, 0 - 5 0C, alcohol, NaBH4, dibutyl amine; (c) p-chlorobenzaldehyde, alcohol, NaOH,RT, actone, 60 OC.
Instead of reducing synthetic steps inventors have also used an alternate of chlorine gas for chlorinating 9H-fluorene. To increase the throughput and quality of Lumefantrine inventors have used different experimental conditions and different solvents and or mixture thereof in different proportions. The above invention is being exemplified by suitable examples which are described as follow

Example-1
Preparation of 2, 7 - Dichloro - 9H fluorene (4): Commercially available 9H - fluorene of formula 3 (50 gm, 0.30 mol) is dissolved in dichloromethane (400 ml) at 25 - 30 0C. The mixture is cooled to 18 - 20 0C and 4 equivalents of sulfuryl chloride, already diluted with dichloromethane (200 ml), is added over 1-1.5 hrs. The reaction mixture is agitated for 3 - 4 hrs at 30 - 35 0C. Dichloromethane is distilled off under reduced pressure at 30 - 35 OC.The excess of sulfuryl chloride is distilled off under reduced pressure at 60 OC. The resultant residue is charged with n - hexane (100 ml) and slowly cooled to 15 - 20 0C agitated to 30 minutes then filtered and washed with n - hexane (100 ml) and sucked properly. The wet cake is slurry washed with 5% aqueous soda ash solution (50 ml) followed by purified water (100 ml) and the material is dried under reduced pressure at 40 - 45 0C for 6 - 8 hrs. The achieved yield (42.43 gm) 60 % of HPLC purity 99 % and MR 122 - 124 0C.
Example-2
Preparation of 2 - Dibutylamino - 1 - (2, 7 - Dichloro - 9H fluoren — 4 — yl) — ethanol (8):
A solution of A1C13 (28.9 gm, 0.217 mol) is prepared in dichloromethane (120 ml) at 25
- 30 0C under anhydrous condition then slowly added chloro acetylchloride (20.88 gm,0.185) and mixture agitated for 30 minutes at the same temperature. The above mixture is cooled to - 5 0C and meanwhile solution of 2, 7 - Dichloro - 9H fluorene (4) (30 gm, 0.128 mol) in dichloromethane (150 ml) prepared at RT. The solution of compound (4) is added in to the reaction mixture at - 5 to 0 0C within 30 - 45 minutes and resultant reaction mass agitated for 3 - 4 hrs at - 5 to 0 0C. When reaction is completed the mass quenched in to already prepared ice, water and HC1 mixture and agitated for 30 - 45 minutes at 0 - 10 0C. Reaction mass settled, separated and aqueous layer extracted with dichloromethane (30 ml). Both the organic layer washed with purified water (60 ml) and organic layer dehydrated with sodium sulfate and concentrated at reduced pressure below 35 0C. Ethanol (30 ml) charged in the mass and distilled completely at 40 - 45 0C under reduced pressure to traces of dichloromethane. The concentrated mass cooled to 25 - 30 0C and charged ethanol (150 ml), stirred and again cooled to - 5 0C then added lot wise sodium borohydride (1.65 gm, 0.044 mol) in 30 - 45 minutes at - 5 to 0 0C. The reaction mass maintained for 1 - 2 hrs at aforesaid temperature. When reaction completed temperature raised to 30 0C and maintained for 30 minutes. After maintaining slowly added dibutylamine (49.2 gm, 0.381 mol) in 20 minutes at 25 - 30 0C. After addition of dibutylamine reaction mass heated to 75 - 80 0C and ethanol distilled off. Again temperature raised to 140 - 145 0C and maintained for 3
- 4 hrs then cooled to 90 0C and charged 10 % aqueous solution of NaOH (36 ml) and finally cooled the mass to RT. Reaction mixture settled, separated and organic layer washed with salt solution (36 ml). The resultant organic layer is concentrated under

reduced pressure at 75 OC, cooled to 60 0C and added ethanol (60 ml) and then cooled to 0 OC. The reaction mixture agitated 1 hr, filtered, washed with ethanol (60 ml) and dried at 45 OC under vacuum over 4 - 5 hrs to yield (35.32 gm) 68.14 % of HPLC purity 98% and MR 74-76 OC.
Prepared a solution of chloroacetylchloride (6.96 gm, 0.062 mol) and A1C13 (8.5 gm, 0.064 mol) in dichloromethane (50 ml) at RT and cooled to - 5 0C. Prepared solution of 2, 7 - Dichloro - 9H fluorene (4) (10 gm, 0.0425 mol) in dichloromethane (50 ml) at RT. The solution of (4) is added into the above solution in 1.25 hrs at - 5 to - 3 0C and mixture is agitated for 2 - 3 hrs at - 5 to 0 0C and quenched with 15% HC1 solution at RT and stirred 15 minutes. Reaction mass settled and separated. Aqueous layer extracted with dichloromethane and organic layer washed with purified water and both the organic layers combined and dehydrated over sodium sulfate and concentrated at 38 0C. Above mass is charged with methanol (20 ml) and striped out completely at 45 0C. The thick mass diluted with methanol and cooled to - 5 0C followed by portion wise addition of sodiumborohydride (0.54 gm, 0.0143 mol) in 1 hr at - 5 to 0 0C and maintained for 3 - 4 hrs. Raised temperature to RT and added dibutylamine (16.47 gm, 0.1274 mol) and distilled out methanol. Again raised temperature to 140 0C and maintained 3-4 hrs. Reaction mass cooled to 90 0C and quenched with 10% caustic solution (12 ml) then cooled at RT and separated layer. Organic layer concentrated at 75 0C under vacuum and charged methanol at 50 0C, cooled to 0 0C, stirred for 1 hr filtered, washed with methanol (20 ml) and dried at 45 0C under vacuum over 4 - 5 hrs to yield (10.97 gm) 63.5 % of HPLC purity 95% and MR 72 - 74 0C.
Example-3
Preparation of Lumefantrine or 2-Dibutylamino-l-{2, 7-dichIoro-9-[l-(4-chIorophenyl)
meth-(Z)-ylidene]-9H-fluoren-4-yl}ethanol (1):
Prepared solution of 2 - Dibutylamino - 1 - (2, 7 - Dichloro - 9H fluoren — 4 — yl) — ethanol (20 gm, 0.049 mol) and NaOH (3.95 gm, 0.098 mol) in ethanol (160 ml) at RT. Prepared Solution of p - chlorobenzaldehyde (7.93 gm, 0.057 mol) in ethanol (80 ml) at RT and added in to the above solution at RT. Resultant reaction mixture slowly heated to 70 0C within 1 hr afterward cooled to 38 0C within 1 hr and agitated 4 - 6 hrs strictly at 38 0C then cooled to RT, filtered and washed with ethanol (40 ml) and subjected to purification by charging into acetone (160 ml). The mass is refluxed for 2 hrs at 60 0C and filtered. The filtrate cooled to 20 - 25 0C, agitated 30 minutes, filtered, washed with acetone (40 ml) and dried under vacuum at 45 0C over 4 - 5 hrs to yield (16.92 gm) 65.0 % of HPLC purity 99.77% and MR 126 - 128 0C.
Prepared solution of 2 - Dibutylamino - 1 - (2, 7 - Dichloro - 9H fluoren — 4 — yl) — ethanol (5 gm, 0.0123 mol) and NaOH (0.98 gm, 0.0244 mol) in methanol (60 ml) at RT and added p - chlorobenzaldehyde (1.89 gm, 0.0135 mol). The reaction mixture stirred for 14 - 16 hrs at 35 0C then cooled to RT and crude isolated which refluxed with acetone (40 ml) for 1.5 hrs filtered and filtrate cooled to RT and isolated material to yield (3.91 gm) 60.0 % of purity 99.36% and MR 127 - 129 0C.

We claim:-
1. An industrially feasible and cost effective process for preparation of
Lumefantrine, or 2-dibutylamino-1 - {2,7-dichloro-9-[1-(4-chlorophenyl)meth-(Z)-
ylidene]-9H-fluoren-4-yl} ethanol and intermediate thereof, comprising the
following steps of:
Conversion of 9-H fluorine in to 2,7 - dichloro-9H-fiuorine by sufuryl chloride using
dichloromethane as a solvent.
In situ conversion of 2,7 - dichloro-9H-fluorine of in to 2-Dibutylamino-l-(2,7-
dichloro-9H-fluoren-4-yl)ehanol.
Conversion of 2-Dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ehanol in to 2-
Dibutylamino-l-{2, 7-dichloro-9-[l-(4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-
yl}ethanol by condensing p-chlorobenzaldehyde.
Purification of crude lumefantrine by new method using acetone for high yield and
quality.
2. Aprocess as clamed in claim 1, wherein the (step-a) preparation of 2.7-dichloro-9H-fluorene, 4, from 9H-fluorene,3, sulfuryl chloride using as achlorinating agent and di-chloro methane as a solvent comprising the steps of,
preparing a solution of 9H-fluorene in dichloromethane,
adding chlorinating agent in 1 - 1.5 hrs at 18 - 20 0C,
maintaining reaction 3 - 4 hrs at 18 - 20 0C,
separating solvent by simple distillation and or distillation at reduced pressure,
crystallization of material by solvent and
finally washing with SBC solution purified water to get more than 60% yield and more
than 99% purity.
3. A process as claimed in claim 1, wherein the 2-Dibutylamino-1 -(2,7-dichloro-9H-fluoren-4-yl)ehanol,8, from 2,7-Dichloro-9H-fluorene,4, prepared in situ without isolation of 2-Chloro- l-(2,7-dich]oro-9H-fluoren-4-yl)ehanone,5 comprising the following steps,
preparing a solution of chloroacetyl chloride in dichloromethane in the presence of
AIC13,
preparing a solution of 2,7-Dichloro-9H-fluorene in dichloromethane,
adding the solution of step b into step (a) at - 5 to 0 0C, in 45 minutes,
agitating mass of step c, until reaction complies, (3-4 hrs) at - 5 to 0 0C,
quenching the mass of step d into already prepared ice, water and HCI mixture after that
layer separation, extraction of aqueous layer washing and dehydration of organic layer
performed,
concentrating the mass under reduced pressure at 30 - 35 0C and the resultant is 5 used in
situ,

preparing solution of above mass in different alcoholic solvents or in mixture thereof, most preferably methanol and ethanol followed by lot wise addition of sodium at - 5 to 0 OC, in 45 minutes,
agitating mass of step g, until reaction complies,(l - 2 hrs) at - 5 to 0 OC, Adding dibutyl amine at 25 - 30 OC and distilled off solvent at atmospheric pressure within 1 hr,
Heating the mass to 145 0C and agitating 3 - 4 hrs at the same temperature. Cooling it to 90 OC and quenching with 10% aqueous caustic solution followed by cooling to RT layer separation,
Washing the organic layer with salt solution and concentrating it under reduced pressure at 75 OC,
adding alcoholic solvents, most preferably methanol and ethanol, or mixture thereof in the above mass and cooling to 0 OC and
agitating the above mass for 1 hr filter the solid and wash solvent used in step m
4. A process as claimed in claim 1, wherein the 2-Dibutylamino-l-{2, 7-dichloro-
9-[l-(4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-yl}ethanoI, 1 , from 2-Dibutylamino-l-(2,7-dichloro-9H-fluoren-4-yl)ehanol,8, and E/Z - isomers 9 and 1 are isolated by the Knoevenagel type of condensation of p-Chlorobenzaldehyde, under the conditions of,
a) preparing basic solution of 2-Dibutylamino-l-(2,7-dichloro-9H-fluQren-4-yl)ehanol,8 with the help of NaOH in alcoholic solvents or in mixture thereof, most preferably methanol and ethanol at room temperature,
b) preparing solution of p - chlorobenzaldehyde in alcoholic solvents or in mixture thereof, most preferably as used in step a, at RT,
c) adding solution of step b into solution of step a at RT,
d) increasing the temperature of reaction mass to 70 OC within 1 hr followed by
cooling to 38 OC within 1 hr,(this is the key step to get desired Z - isomer, 1,)
e) agitating the mass until reaction complies,4 - 6 hrs, strictly at 38 OC,
f) cooling the reaction mixture to 25 - 30 0C, filter and wash with solvent, same as used in step a and b, to get the crude 2-Dibutylamino-l-{2, 7-dichloro-9-[l-(4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-yl} ethanol, 1 .
5) A process as claimed in claim 1, wherein the purification and recrystallization of
Lumefantrine or 2-Dibutylamino-l-{2, 7-dichloro-9-[1-4-chlorophenyl) meth-(Z)-ylidene]-9H-fluoren-4-yl}ethanol, 1,has been performed under the condition of,
a) heating the mixture of crude and acetone up to reflux and
agitating for 2 hrs,
b) separating undesired impurities by filtration at 60 0C followed by cooling the filtrate to 20 - 25 0C,
c) filtering and washing the product with acetone to get more that 65% yield and more than 99.77% purity.