"Novel Process For The Preparation Of 2,7 Dichlorofluorene"

Abstract

The  present  invention  relates  to  a  novel  process  for  nation  of 2,7-dichlorofluorene which is a key intermediate in the preparation of the anti-malarial drug lumefantrine.

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Specification

The present invention relates to a novel process for the preparation of 2,7-dichlorofluorene which is a key intermediate in the preparation of the anti-malarial drug lumefantrine.
Lumefantrine earlier known as Benflurnetol or Benzfluorenol is chemically (Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]]-9H-fluorene-4-methanol having the structural formula I.
(Figure Remove)
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. Artemether + Lumefantrine, a fixed dose combination of two active ingredients, artemether (a sesquiterpene lactone derivative of a naturally occurring substance artemisinin), and lumefantrine (a synthetic fluorene derivative) is 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 P. falciparum or mixed infections including P. falciparum-the deadliest form of the disease. The combination has gametocytocidal action.
P.falciparum and P.virax 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, P. falciparum is the dominant parasite species and almost all malaria deaths happen due to infections by this species. Moreover, the biological diversity of P. falciparum, its ability to develop
resistance to a number of anti-malarial drugs has been a major challenge in malaria chemotherapy.
Chinese Patent No. 109680 discloses a process for the preparation of 2,7-dichlorofluorene which involves bubbling chlorine gas through a solution of fluorene in glacial acetic acid in the presence of ferric chloride. The above method suffers from the disadvantage that chlorine is highly reactive and dangerous to handle. Moreover chlorine is irritating and has a strong, pungent odour which makes it less favourable to employ it on an industrial scale.
Journal of Organic Chemistry 45(21), 4250-4252, (1980) discloses a process for the preparation of 2,7-dichlorofiuorene by reacting a solution of fluorene in acetic acid with N-chlorosuccinimide. N-chlorosuccinimide is a costly reagent and it is desirable to explore the workability of alternate reagents which are cheaply available.
Our co-pending Indian patent application No 1884/DEL/2006 discloses process for preparation of Lumefantrine wherein the intermediate 2,7-dichlorofluorene is prepared by chlorination of fluorene using hypochlorite.
In view of the practical difficulties and high cost associated with the known processes, alternate process for the preparation of 2,7-dichlorofluorene is desired which is cost effective, convenient to operate with ease of handling the reagents and also provides 2,7-dicholorofluorene in good yield and high purity.
The present inventors have developed a novel process for the preparation of 2,7-dichlorofluorene which involves chlorinating fluorene using sulfuryl chloride. 2,7-dichlorofluorene is a key intermediate in the synthesis of the antimalarial drug lumefantrine. The present process affords 2,7-dichlorofluorene in good yield and high purity and is easily scalable.
A first aspect of the present invention provides a process for the preparation of 2,7-dichlorofluorene of Formula III,

l
wherein the said process comprises of, a) reacting fluorene of Formula II,

(Figure Remove)
with sulfuryl chloride,
b) isolating 2,7-dichlorofluorene of Formula III from the reaction mass thereof.
Fluorene of Formula II is dissolved in a suitable organic solvent at about 20°C to 35°C. The above mixture can be optionally acidified using an acid. To the resultant mixture sulfuryl chloride (2 equivalents) is added dropwise over 1-2 hours. The reaction mixture is stirred for 1 to 3 hours at about 20°C to 35°C. The stirred mixture is heated to about 40-50°C to recover the organic solvent. The resultant mixture is further heated to about 80-90°C to recover excess sulfuryl chloride. The residue so obtained was charged with hexanes and the resultant mixture stirred for about 0.5-1 hour and then filtered and washed with hexanes. The wet cake so obtained was charged into deionized water and the pH adjusted to about 7-8 using a base. The resultant mixture was stirred for about 5-10 minutes and the solid so obtained was filtered, washed with deionized water and dried to obtain 2,7-dichlorofluorene of Formula III.
Alternatively 2,7-dichlorofluorene of Formula III can be prepared by the following method. Fluorene of Formula II is dissolved in a suitable organic solvent at about 20°C to 40°C. The above mixture can be optionally acidified using an acid. To the resultant mixture sulfuryt chloride (4 equivalents) is added dropwise over 1-2 hours. The reaction mixture is stirred for 1 to 3 hours at about 20°C to 40°C. The stirred mixture is cooled to about -10°C to +10°C and charged with distilled water. The pH of the resultant mixture is adjusted to about 7-8 with a base and the mixture stirred

for 5-10 minutes. The organic layer is first washed with deionized water and brine solution and then distilled off. The residue so obtained is charged with hexanes and the mixture cooled to 5°C to 15°C, filetered, washed with hexanes and dried to obtain 2,7-dichlorofluorene of Formula III.
The present process provides 2,7-dichlorofluorene of Formula III in good yield and high purity. 2,7-dichlorofluorene of Formula III obtained by the process of the present invention can be converted to lumefantrine by methods known in the art or by the process exemplified in the present invention. Suitable organic solvents can be selected from the group comprising of chlorinated hydrocarbons, esters and the like or mixtures thereof. The chlorinated hydrocarbons can be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or mixtures thereof. The esters can be selected from ethyl acetate, propyl acetate, isobutyl acetate and the like or mixtures thereof. Suitable acids can be selected from inorganic or organic acids such as for example hydrochloric acid, sulfuric acid, p-toluenesulphonic acid and the like or mixtures thereof. Suitable bases can be selected from the group comprising of sodium hydroxide, potassium hydroxide and the like or mixtures thereof.
A second aspect of the present invention provides a process for the preparation of Lumefantrine of Formula I,

wherein the said process comprises of, a) reacting fluorene of Formula II,

with sulfuryl chloride, to obtain 2,7-dichlorofluorene of Formula III,

b) reacting 2,7-dichlorofluorene of Formula III with a compound of Formula IV,
0

wherein X and X' may be the same or different and each represents a leaving group, to obtain a compound of Formula V,

wherein X' is as defined above,
c) reducing the compound of Formula V with a reducing agent to form a compound
of Formula VI,
d) reacting the compound of Formula VI with di-n-butyl amine to obtain a compound of Formula VII,

Cl


Ve) reacting the compound of Formula VII with p-chlorobenzaldehyde in the presence
of a base to obtain Lumefantrine of Formula I,
f) isolating Lumefantrine of Formula I from the reaction mass thereof.
2,7-dichlorofluorene of Formula III can be obtained by the process disclosed in the first aspect of the present invention. 2,7-dichlorofluorene of Formula III can be converted to Lumefantrine of Formula I by methods known in the art or according to the process of the present invention. 2,7-dichlorofluorene of Formula III is treated with a compound of Formula IV to obtain a compound of Formula V. Compound of Formula V is reduced with a suitable reducing agent to form the oxirane derivative of Formula VI in situ which is then reacted with di-n-butyl amine to obtain a compound of Formula VII. Alternatively oxirane derivative of Formula VI can be isolated and then reacted with di-n-butyl amine to obtain a compound of Formula VII. Compound of Formula VII is then treated with p-chlorobenzaldehyde in the presence of a base to obtain lumefantrine of Formula I. The base employed in step e) is known to a person of ordinary skills in the art and for example can be selected from sodium hydroxide, potassium hydroxide and the like or mixtures thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF 2,7-DICHLOROFLUORENE
Fluorene (50 g) was charged into dichloromethane (250 ml) at 25-30°C and to the resultant mixture sulfuryl chloride (166 g) was added dropwise over 1.5 hours at 25-30°C. The reaction mixture was stirred for 2 hours at 25-30°C and cooled to 0-5°C and charged with pre-chilled distilled water (100 ml). The pH of the resultant mixture was adjusted to 7-8 by dropwise addition of sodium hydroxide solution (20%, 300ml) over 30-40 minutes and the mixture stirred for 5 minutes. The organic layer was first washed with deionized water (2 x 200ml) and brine solution (30%, 100ml x 1) and then distilled off completely. The residue was charged with hexanes (40 ml) over 10 minutes and the resultant mixture cooled to 10-15°C. The solid so obtained was filtered, washed with hexanes (2 x 20ml) and dried at 50-55°C for 6 hours to afford the title compound. Yield: 37.12g (52%) Purity: 99.25 % (by HPLC)
EXAMPLE 2
PREPARATION OF 2,7-DICHLOROFLUORENE
Fluorene (25 g) was charged into dichloromethane (100 ml) at 25-30°C and to the resultant mixture sulfuryl chloride (91 g) was added dropwise over 1.5 hours at 25-30°C. The reaction mixture was stirred for 2 hours at 25-30°C and heated to 40-45°C to distill off dichloromethane. The resultant mixture was further heated to 80-85°C to recover excess sulfuryl chloride and the last traces were recovered under mild vacuum. The residue so obtained was charged with hexanes and the resultant mixture stirred for 0.5 hour, filtered and washed with hexanes (2 x 10ml). The wet caked was charged into deionized water (50 ml) and the pH of the resultant mixture was adjusted to 7-8 by dropwise addition of sodium hydroxide solution (20%, 20ml). The mixture was stirred for 5 minutes and the solid so obtained was filtered, washed with deionized water (2 x 20ml) and dried at 50-55°C for 14 hours to afford the title compound. Yield: 17.15g(49%) Purity: 99.43 % (by HPLC)
EXAMPLE 3
PREPARATION OF 2,7-DICHLOROFLUORENE
Fluorene (20 g) was charged into dichloromethane (100 ml) at 25-30°C. To this mixture was added concentrated hydrochloric acid (7 ml) at 25-30°C. To the resultant mixture sulfuryl chloride (56 g) was added dropwise over 20 minutes at 25- 30°C. The reaction mixture was stirred for 6 hours at 25-30°C and cooled to 5-10°C. The pH of the resultant mixture was adjusted to 7 with sodium hydroxide solution (4%, 160ml). The organic layer was washed with deionized water (2 x 100ml), dried with sodium sulfate and evaporated completely under vacuum at40-45°C, The residue so obtained was charged with hexanes (20 ml) and the resultant mixture stirred for 0.5 hour, cooled to 5-10°C and stirred further for 0.5 hour. The solid so obtained was filtered, washed with pre-chilled hexanes (2 x 10ml) and dried at 50-55°C for 7 hours to afford the title compound. Yield: 12.3g(43%) Purity: 96.91 % (by HPLC)
EXAMPLE 4
PREPARATION OF 2-CHLORO-1-(2,7-DICHLORO-9H-FLUOREN-4-
YL)ETHANONE
Chloroacetylchloride (14.5 g) was charged into dichloromethane (75 ml) at 25-30°C and the mixture cooled to 0-5°C. To the cooled mixture anhydrous aluminium chloride (25.5g) was slowly added at 0-5°C over 25-30 minutes. The resultant mixture was stirred at 0-5°C for 0.5 hour. To the stirred mixture a solution of 2,7-dichlorofluorene in dichloromethane (25 g in 70 ml) was charged at 0-5°C. The reaction mixture was stirred for 4 hours at 0-5°C and monitored by thin layer chromatography. The mixture was slowly charged into pre-chilled hydrochloric acid (250 ml, 1N) at 0-20°C over 20 minutes. The resultant mixture was stirred for 10 minutes at 25-30°C. The aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers were washed with deionized water (2 x 100 ml) and dichloromethane distilled off completely under vacuum. The resultant mass was charged with denatured spirit (200 ml) and 50 ml of denatured spirit was distilled off. The suspension so obtained was stirred for 4 hours at 25-30°C and then cooled to 0-
5°C and stirred for 1 hour. The solid so obtained was filtered, washed with pre-chilled denatured spirit (25 ml) and dried at 50- 55°C to afford the title compound. Yield: 28.35g (85.9%) Purity: 93.21% (by HPLC)
EXAMPLE 5
PREPARATION OF 2-(di-n-BUTYLAMINO)-1-(2,7-DICHLORO-9H-FLUOREN-4-YL)ETHANOL
2-chloro-1-(2,7-dichloro-9H-fluoren-4-yl)ethanone (25 g) was charged into ethanol (250 ml) at 25-30°C. To the above mixture sodium borohydride (3.5 g) was charged slowly over 75 minutes at 30-35°C. The reaction mixture stirred for 6 hours at 30-35°C and cooled to 0-5°C and stirred further for 1 hour. The resultant mixture was filtered and dried under suction. The wet cake was taken in ethanol (35 ml) at 25-30°C and charged with di-n-butylamine (12.25 g). The temperature of the reaction mixture was raised to 80-85°C and the reaction mixture stirred for 14 hours, cooled to 40-45°C and charged into deionized water (250 ml). The resultant mixture was extracted using dichloromethane (1 x 75 ml + 2 x 35 ml). The combined organic layers were charged with hydrochloric acid (1 x 75 ml) and the resultant mixture stirred for 0.5 hour. The organic layer was washed with deionized water (2 x 75 ml), charged with carbon (1.25 g) and stirred for 1 hour at 25-30°C. The resultant mixture was filtered through hyflow bed and the bed washed with dichloromethane (1 x 25 ml). The dichloromethane was evaporated completely under vacuum. The residue so obtained was charged with ethanol (35 ml) and the temperature of the mixture raised to 50-55°C. The solution so obtained was stirred for 3 hours at 25-30°C, cooled to 0-5°C and stirred for 1 hour. The solid so obtained was filtered, washed with pre-chilled ethanol (2x12 ml) and dried at 45-50°C for 14 hours to afford the title compound. Yield: 14.35g(51%) Purity: 99.94% (by HPLC)
EXAMPLE 6
PREPARATION OF 2-(di-n-BUTYLAMINO)-1-(2,7-DICHLORO-9H-FLUOREN-4-YL)ETHANOL
2-chloro-1-(2,7-dichloro-9H-fluoren-4-yl)ethanone (25 g) was charged into absolute ethanol (150 ml) at 25-30°C. To the above mixture sodium borohydride (3.25 g) was charged slowly over 40 minutes at 25-35°C. The reaction mixture was stirred for 8 hours at 25-30°C and monitored by Thin Layer Chromatography (TLC). After TLC showed completion of reaction, the resultant mixture was charged with di-n-butylamine (12.25 g) at 25-30°C. The temperature of the reaction mixture was raised to 75-80°C and the reaction mixture stirred for 14 hours at 75-80°C and then cooled to 60-65°C. The resultant mixture was filtered through hyflo bed while hot. The filtrate was evaporated under vacuum at 50-52°C to remove ethanol (50 ml). The resultant mixture was cooled to 25-30°C and stirred for 3 hours at 25-30°C and further cooled to 0-5°C and stirred for 1 hour at 0-5°C. The stirred mixture was filtered and washed with deionized water (1x10 ml) and dried at 45-50°C for 6 hours to afford the title compound. Yield:21.5g(67%) Purity: 94.61% (by HPLC)
EXAMPLE 7
PREPARATION OF 2-(DIBUTYLAMINO)-1-[2,7-DICHLORO-9-(4-CHLOROBENZYL-IDENE)-9H-FLUOREN-4-YL]ETHANOL
Sodium hydroxide (3.5 g) was charged into ethanol (250 ml) at 25-30°C and the mixture stirred for 0.5 hour to get a clear solution. The above solution was charged with 2-(di-n-butylamino)-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol (10 g) at 25-30°C. The resultant mixture was stirred for 15 minutes at 25-30°C and charged with 4-chlorobenzaldehyde (4.0 g) at 25-30°C. The reaction mixture was stirred for 24 hours at 25-30°C and cooled to 20-25°C and stirred for 1 hour. The solid so obtained was filtered, washed with ethanol (1 x 10 ml) and deionized water (4 x 60 ml) and then dried at 50-55°C under vacuum to afford the title compound. Yield: 9.95g (76.5%) Purity: 99.48% (by HPLC)

WE CLAIM:
1. A process for the preparation of 2,7-dichlorofluorene of Formula

wherein the said process comprises of, a) reacting fluorene of Formula II,

with sulfuryl chloride,
b) isolating 2,7-dichlorofluorene of Formula III from the reaction mass thereof.
2. A process for the preparation of Lumefantrine of Formula I,

wherein the said process comprises of, a) reacting fluorene of Formula II,
(Figure Remove)
b) reacting 2,7-dichlorofluorene of Formula III with a compound of Formula IV,
wherein X and X' may be the same or different and each represents a leaving group, to obtain a compound of Formula V,

wherein X' is as defined above,
c) reducing the compound of Formula V with a reducing agent to form a compound of
Formula VI,
d) reacting the compound of Formula VI with di-n-butyl amine to obtain a compound of Formula VII,
e) reacting the compound of Formula VII with p-chlorobenzaldehyde in the presence of a
base to obtain Lumefantrine of Formula I,
f) isolating Lumefantrine of Formula I from the reaction mass thereof.
3. The process according to claim 1 and 2 wherein step a) is carried out in the presence
of a solvent selected from the group comprising of chlorinated hydrocarbons, esters or
mixtures thereof.
4. The process according to claim 3 wherein the chlorinated hydrocarbon is selected from
the group comprising of dichloromethane, dichloroethane, chloroform, carbon
tetrachloride or mixtures thereof.
5. The process according to claim 4 wherein the chlorinated hydrocarbon is
dichloromethane.
6. The process according to claim 2 wherein X and X' are chlorine.
7. The process according to claim 2 wherein the oxirane derivative of Formula VI is
reacted in situ with di-n-butyl amine to obtain the compound of Formula VII.
8. The process according to claim 2 wherein the oxirane derivative of Formula VI is
isolated and then reacted with di-n-butyl amine to obtain the compound of Formula VII.
9. The process according to claim 1 and 2 wherein step a) is carried out optionally in the
presence of an acid.

10. The process according to claim 9 wherein the acid is selected from inorganic or organic acid.