FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10, rule 13]


IMPROVED 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 describes the invention.


TITLE
Improved Process for the Synthesis of Lumefantrine
FIELD OF THE INVENTION
The present invention relates to an improved process for the synthesis of (Z)-2-(dibutylamino)-l-(2,7-dichloro-9-(4-chlorobenzylidene)-9//-fluoren-4-yl)ethanol, commonly known as Lumefantrine, an antimalarial drug. More particularly, the present invention relates to improved processes for the selective synthesis of Z-isomer of 2-(dibutylamino)-1 -(2,7-dichloro-9-(4-chlorobenzylidene)-9//-fluoren-4-yl)ethanol. The present invention can also be applied to suitably substituted fluorene derivatives & in particular those with substituent at 2,4 & 7-position in the fluorene ring.
BACKGROUND OF THE INVENTION
(Z)-2-(Dibutylamino)-l-(2,7-dichloro-9-(4-chlorobenzylidene)-9//-fluoren-4-yl)ethanol of Formula I, commonly known as Lumefantrine (formerly known as Benflumetol), belongs to the class of antimalarial agents.


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 CN 1042535 discloses the synthesis of lumefantrine as shown in Scheme I. 2-(2,7-Dichloro-9H-fluoren-4-yl)oxirane is reacted with dibutyl amine, which is further reacted with p-chlorobenzaldehyde in ethanol in presence of sodium hydroxide to give Lumefantrine of formula I (Scheme I)

,95% and in the final product is >99%.
In yet another embodiment of the present invention, the step (1) of process A and process B is carried out at room temperature and the reaction time ranges from 1 to 5 hrs, preferably from 1 to 2 hrs.
In another embodiment of the present invention, the step (2) of process A and process B is carried out at a temperature between 30°C to 80°C, preferably between 40°C to 60°C and the reaction time ranges from 2 to 6 hrs, preferably from 2 to 4 hrs.

In another embodiment of the present invention, there is provided a process, which can be applied to suitably substituted fluorene derivatives & in particular those with substituents at 2,4 & 7-position in the fluorene ring (Scheme VI).



Formula III

p-Chlorobenzaldehyde Base, Alcohol, RT



R3HT
Alcohol, 40-60°C

Formula IV
R, Rlt R2 & R3 = H, Cj.jo-straight chain or substituted alkyl, alkene, alkyne aryl, substituted aryl, halides, amines

A
R, R2 & R3 = H, CI; Rj =-CH(OH)CH2Cl,- CH(OH)CH2N(CH2CH2CH2CH3)2 -COCH2Cl,

Scheme VI
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.

Examples:
Process A: Procedure for the synthesis of Lumefantrine [(Z)-2~(dibutyIamino)-l-(2,7-dichloro-9-(4-chlorobenzylidene)-9//-fluoren-4-yl)ethanol]:
Example 1:
To the stirred slurry of 2-(dibutylamino)-l-(2,7-dichloro-9#-fluoren-4-yl)ethanol (lOO.Og, 0.246 moles), 4-chlorobenzaldehyde (39.69g, 0.283 moles) in n-butanol (500ml, 5 vol.) was added sodium hydroxide (11.83g, 0.298 moles). Reaction mixture was stirred at ambient temperature for 1 to 1.5 hrs, and then heated to 40-60°C. After heating for 3-4 hrs, reaction mixture slurry was cooled to 0-5 °C and yellow colored solid was filtered out. It was washed with water. Finally it was dried at 60-70°C to obtain lumefantrine (Yield = 109g (83.84%), Z-isomer = >99%, HPLC purity = 99.67%).
Above obtained product (109g) was taken in n-butanol (763ml, 7.0 vol.) and gradually heated to 80-100°C to make clear solution. It was then filtered while hot & filtrate was then cooled to 0-5°C, Yellow solid crystallized was filtered & dried at 60-70°C. Yield = 105g (96.33% from crude), Z-Isomer = >99%, HPLC purity = 99.9%). *H NMR in CDC13: 5 7.74 (d, 1H, Ar-H), 7.70 (d, 1H, Ar-H) 7.61 (d, 1H, Ar-H), 7.59 (s, 1H, Ar-H), 7.49-7.47 (m, 4H, Ar-H), 7.46 (d, 1H, Ar-H), 7.34 (dd, 1H, Ar-H), 5.38 (dd, 1H, ArCH(OH)CH2N-), 4.55 (brd, 1H, -OH), 2.90 (dd, 1H, CH(OH)CH2N-). 2.73-2.67 & 2.57-2.43 (2 x m, 5H, CH(OH)CHj>N(CH2£)CH2^, 1.54-1.35 (m, 8H, N(CH2CH2CH2CH3)2), 0.99 (t, 6H, 2 x -CH3).
13C NMR in CDC13: 8141.42, 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.

Example-2
To the stirred slurry of 2-(dibutylamino)-l-(2,7-dichloro-9//-fluoren-4-yl)ethanol (25.0g, 0.0615 moles), 4-chlorobenzaldehyde (9.68g, 0.0689 moles) in n-propanol (125ml, 5 vol.) was added sodium hydroxide (2.9g, 0.0738 moles). Reaction mixture was stirred at ambient temperature for 1 to 1.5 hrs; yellowish slurry was then heated to 40-60°C for 3-4 hrs. After heating for 3-4 hrs, reaction mixture was cooled to Q-5°C and yellow colored solid was filtered out. It was washed with water. Finally it was dried at 60-70°C to obtain pure lumefantrine (Yield = 28g (86.15%), Z-isomer = >95%, HPLC purity = >99%).
Process B: Procedure for the synthesis of Lumefantrine [(Z)-2-(dibutylamino)-l-(2,7-dichloro-9-(4-chlorobenzylidene)-9/7-fluoren-4-yl)ethanol]:
Example-1 Preparation:
To the stirred slurry of 2-(dibutylamino)-l-(2,7-dichloro-9i/-fluoren-4-yl)ethanol
(lOO.Og, 0.246 moles), 4-chlorobenzaldehyde (39.69g, 0.283 moles) in n-butanol
(500ml, 5 vol.) was added sodium hydroxide (11.83g, 0.298 moles). Reaction mixture
was stirred at ambient temperature. After 1 to 1.5 hrs, it was cooled to 0-5° C & solid
precipitated was filtered, and suck dried. Wet weight = 144-150g; Z-Isomer = 40-60%.
Isomerization:
Wet cake (144-150g) from above reaction was taken into n-butanol (650 ml) and was
added catalytic amount of sodium hydroxide; the slurry was heated at 40-60° C for 2-4
hrs. After which time, reaction mixture was cooled to 0-5°C and yellow colored solid
was filtered & was washed with water. Finally it was dried at 60-70°C to obtain crude
lumefantrine (Yield = 1 lOg, Z-Isomer = >99%, HPLC purity - >99%).
Purification:
Above crude lumefantrine (llOg) was taken in n-butanol (880ml, 8 vol.) and heated to
80-100 °C to make clear solution. It was then and the filtrate was then gradually cooled

to 0-5° C and yellow solid crystallized was filtered out & dried at 60-70° C. Yield =
104g, Z-Isomer = >99.7%, HPLC purity = >99.9%).
Example-2
Preparation:
To the stirred slurry of 2-(dibutylamino)-l-(2,7-dichloro-9/f-fluoren-4-yl)ethanol
(lO.Og, 0.0246 moles), 4-chlorobenzaldehyde (3.97g, 0.0282 moles) in n-propanol
(SQml, 5 vol.) at room, temperature was. added sodium, hydroxide (i A&g, Q.Q29S m&ies.y
Reaction mixture was stirred at ambient temperature. After 1 to 1.5 hrs, it was cooled to
0-5 °C & yellow colored solid precipitated was filtered out, washed with n-propanol and
suck dried. Yield = lO.Og (dried), Z-Isomer = 40-60%).
Isomerization:
Lumefantrine (lO.Og) from above reaction was taken into n-propanol (50 ml) and was
added catalytic amount of sodium hydroxide; the slurry was heated at 40-60 °C for 2-4
hrs. After which time, reaction mixture slurry was cooled to 0-5 °C and yellow colored
solid was filtered out. It was washed with water. Finally it was dried at 60-70 °C to
obtain lumefantrine (Yield - 9.0g, Z-Isomer = >95%, HPLC purity = >99%).
Purification:
Crude lumefantrine (9.0g) was taken in n-propanol (10 vol.) and heated to 80-100 °C to
make clear solution. It was then filtered and the filtrate was then gradually cooled to 0-5
°C & yellow solid crystallized was filtered out & dried at 60-70 °C. Yield = 8.0g, Z-
Isomer = >99%, HPLC purity = >99.7%).