Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Process for preparation of Atovaquone and polymorph thereof."
2. APPLICANT
(l)NAME: USV LIMITED
(2)NATIONALITY: Indian Company incorporated under the
Companies Act 1956
(3)ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical Field:
The present invention relates to process for preparation of 2-[4-(4-chlorophenyl)-cyclohexyi]-3-hydroxy-l,4-naphthoquinone commonly known as Atovaquone and intermediates thereof. More particularly, the present invention relates to a process for preparation of substantially pure Atovaquone . The present invention further relates to process for preparation of substantially pure Atovaquone Form III.
Background of the invention :

Atovaquone represented by formula (I) is approved and marketed as a prescription drug for the treatment of pneunocystis carinii pneumonia, a common parasitic lung infection of immunocompromised patients and also display potent antimalarial activity. US 4981874 equivalent to US5053432 and EP0362996 discloses a method of preparation of

Atovaquone. The first step of process in US '874 discloses preparation of 4-(4-chlorophenyl)-l-acetyl-cyclohexane(III) by reacting acetyl chloride and finely powdered aluminium chloride in carbon disulphide at -50 °C, in a CO2/oxitol bath. Cyclohexene is added dropwise to the above mixture at below -20°C to get a gummy orange complex. Chlorobenzene is added to the material obtained, the so-obtained solution is quenched in a mixture of ice and concentrated hydrochloric acid and the organic layer separated, washed with 2M hydrochloric acid, 2M sodium hydroxide and water and dried. The product is distilled under vacuum at 140 to 145°C (0.1 mm Hg) and diluted with petroleum ether to recover the solid of compound (III). Purity and overall yield of product (I) is not mentioned. On following this step yield obtained is only 10% . The volume of chlorobenzene used is high (1:12) with respect to cyclohexene. The compound of formula (III) is further oxidized using sodium hypobromite solution to provide solid of compound (IV) which is further recrystallized from ethanol to give 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV). In this step carbon disulphide is used which is extremely flammable and gives off highly poisonous vapor and inhalation of the vapor over a period may cause severe damage to the nervous system, including failure of vision, mental disturbance and paralysis. Moreover, conventional batch vacuum distillation as followed in US '874 for
2

purification of the intermediate product requires longer distillation time, larger condenser surface area, prolonged exposure of feed to heat leading to decomposition, formation of impurities and low yield of the product.
The second step for preparing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) comprises condensing 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV), 2- chloro-1,4-naphthoquinone (V) and silver nitrate in a mixture of acetonitrile sulpholane and water. In this process total volume of solvents used is 20 to 22 times per gram of 4-(4-chlorphenyl) cyclohexane-1-carboxylic acid to yield crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l,4-naphthoquinone (VI). The crude product obtained is recrystallized with acetonitrile (15 to 20 volumes) to isolate the pure solid product (VI) (yield 12%).
In third step, the compound (VI) is hydrolyzed by potassium hydroxide in presence of methanol to provide 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone of formula (I). The trans isomer of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone is achieved by recrystallizing the compound (I) using acetonitrile. To get the compound (I) in pure form multiple recrystallization of intermediates is required which makes the process uneconomical and the overall yield of the product obtained is less by following the process as described in US '874. The reaction is represented by the scheme as shown below. Scheme-I

US4514044 teaches the process for preparation of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III). According to the example 1 of US '044, mixture of acetyl chloride and cyclohexene is added to mixture of chlorobenzene and aluminium chloride, after completion of reaction the
3

reaction mixture is quenched in 1:1 hydrochloric acid, the separated organic layer is extracted with petroleum ether and solvent is evaporated to get oily substance which is subjected to distillation under reduced pressure at 120 to 130°C (0.1 mm Hg). To the obtained fraction 1:1 mixture of methanol and ethanol is added to obtain crude crystals which are purified by recrystallizing with methanol to get compound (III) with yield of 12%. In this process vacuum distillation under reduced pressure for isolating the intermediate product requires longer distillation time, larger condenser surface area and reduces the yield of the product.
Drawbacks of the above processes are:
(1) Use of carbon disulphide is extremely flammable and gives off highly poisonous vapor and inhalation of the vapor over a period may cause severe damage to the nervous system, including failure of vision, mental disturbance and paralysis, thus unsafe to use.
(2) Conventional batch vacuum distillation have longer distillation time, requires larger condenser surface area, prolonged exposure of feed to heat leading to decomposition, formation of impurities and low yield, thus the process is inefficient and low yielding.
(3) Higher volume of solvents used in condensation of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) with 2- chloro-l,4-naphthoquinone (V) increase the batch volume, reduce batch size and productivity.
(4) Multiple acetonitrile purification are required to yield Atovaquone as per USP specification which still does not provide Atovaquone in high purity thus process is redundant due to inability to provide Atovaquone in high purity and uneconomical due to poor yield.
In these procedures as mentioned above purification of the final product and intermediates require multiple recrystallization with acetonitrile, which makes the process tedious and time consuming and also increase the solvent requirement of the process. The purity and yield of the product is not mentioned. The cis-trans ratio of the product is also not reported. Further, these processes are not suitable for industrial scale for the production of Atovaquone and are uneconomical. Thus, there is need to develop a process for preparing pure trans Atovaquone with significant selection of the proper solvents and conditions to provide the product with high yield and purity and inhibiting the formation of cis impurity during the manufacturing process. The present invention attempts to overcome the above mentioned drawbacks of the prior art. Considerable investigations have been carried out by the present inventors in efforts to ameliorate the problems as described above by developing the process for preparation of
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substantially pure Atovaquone.
Polymorphs of the Atovaquone are not reported in US4981874 or US5053432. Three polymorphic forms of Atovaquone, Form I, Form II and Form III, are reported in WO2006008752. The polymorphic Form of Atovaquone obtained by the process as disclosed in the US4981874 is designated as Form I in WO2006008752. Another process disclosed in WO2006008752 to prepare Form III uses a mixture of solvents i.e solvent and anti solvent combination. The use of such solvent combination is commercially not viable, as it requires large volume of anti-solvent. The single solvent crystallization disclosed in WO 752 where the volume to solid ratio is very high. The large volume requirement also reduces the batch size. The recovery is many times difficult which in turn increases the production cost.
Hence the present invention also provides process for preparing the polymorphic Form III of Atovaquone, whereby the desired product obtained is in good yield and high purity by simple economic method.
Objects of the invention:
The main object of the present invention is to provide process for the preparation of
substantially pure 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone
(Atovaquone) with high yield and purity.
Another object of the invention is to provide process for preparation of pure Atovaquone Form III avoiding the formation of highly viscous material formed during recrystallization process to get Atovaquone Form III.
Summary of the invention:
The present invention discloses industrially realizable and economically preferable process for
preparation substantially pure 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-
naphthoquinone (Atovaquone) which comprises the steps of:
a) reacting cyclohexene (II) with acetyl chloride in presence of lewis acid and chlorobenzene without using carbon disulphide at extremely low temperature of -35 °C to -5 °C to obtain crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane(III);
XI

(II) H3°


O (HI)

b) purifying crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) by continuous short path distillation process and isolating solid of compound (III);
c) oxidizing compound (III) using sodium hypobromite in organic solvent to get 4-(4-chlorophenyl) cyclohexane-l-carboxylic acid (IV);


HO

purifying the obtained 4-(4-chlorophenyl) cyclohexane-l-carboxylic acid (IV) using polar solvent and isolating pure compound (IV);
e) condensing compound (IV) with 2-chloro-l,4-naphthoquinone (V) in a mixture of polar solvents in presence of silver nitrate and ammonium persulphate at 65°C to 85°C to obtain semi solid mass;
f) slurring the semi solid mass obtained in mixture of organic solvents to get pure 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI);


(VI)

g) hydrolyzing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) in polar protic solvent in presence of alkali metal hydroxide to get crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone (I) (Atovaquone);


h) purifying crude Atovaquone by dissolving in an ethereal solvent to get substantially pure Atovaquone.
In one of the key step of the process, conventional batch vacuum distillation is avoided, to get the product in high yield and purity which takes longer distillation time, requires larger condenser surface area, prolonged exposure of feed to heat leading to decomposition, formation of impurities and gives low yield.
Further the less amount of solvent is used in condensation of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) with 2- chloro-l,4-naphthoquinone (V) which decreases the batch volume, increase batch size and productivity. Moreover, to obtain pure trans Atovaquone multiple acetonitrile purifications were required, are also avoided in the present invention. The present invention thus provides process for preparing pure Atovaquone suitable for industrial scale and economically viable to get the product in higher yield and purity.
Another aspect of the invention provides process for preparation of Form III of Atovaquone which comprises the following steps;
a) dissolving crude Atovaquone (I) in an ethereal solvent at an elevated temperature to form a clear solution,
b) cooling the solution to lower temperature to precipitate the solid,
a) redissolving the solid obtained in an ethereal solvent at an elevated temperature,
b) filtering the hot clear solution and adding seeds of polymorphic Form III at an elevated
temperature;
c) stirring the solution for several hours and
d) isolating substantially pure Atovaquone Form III.
Another aspect of the invention provides process for preparation of Form III of Atovaquone which comprises the following steps ;
a) dissolving crude Atovaquone in a aqueous ethereal solvent at an elevated temperature to form a clear solution;
b) cooling the solution followed by stirring at the same temperature for several hours and
c) isolating substantially pure Atovaquone Form III.
Thus the present invention discloses a process to prepare polymorphic form III of Atovaquone which involves the optimized crystallization temperature as a key for the development of a process. Optimizing the temperature condition for seeding to get the solid-state form Form III
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of Atovaquone thereby making the process advantageous and easy to handle during large scale production.
Description of Figures
Figure 1 X-ray powder diffraction diagram of Form III Figure 2: Crystal structure of Atovaquone Form III Figure 3: Crystal structure of Atovaquone Form I
Description of the invention:
The present invention provides process for preparation of substantially pure 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone) of formula (I). According to the present invention, process for the preparation of substantially pure Atovaquone comprises the steps of:
a) reacting cyclohexene (II) with acetyl chloride in chlorobenzene to obtain crude oil 4-(4-chlorophenyl)-1 -acetyl-cyclohexane(III),

b) purifying crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) by short path distillation and isolating solid of compound (III),
c) oxidizing compound (III) to 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV),

d) purifying 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) using polar solvent,
e) condensing (IV) with 2-chloro-l,4-naphthoquinone (V) in a mixture of polar solvents in presence of a silver nitrate and further treating with ammonium persulphate to obtain 2-
8

[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-1,4-naphthoquinone (VI),

o
f) hydrolyzing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) in polar protic solvent in presence of alkali metal hydroxide and obtaining crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone(I) (Atovaquone) and

g) purifying crude Atovaquone (I) from ethereal solvent to get substantially pure Atovaquone.
In preferred aspect of the present invention, preparation of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) comprises the following steps:
a) addition of acetyl chloride and cyclohexene (II) to a mixture of chlorobenzene and lewis acid at extremely low temperature,
O
(II)
b) raising the temperature of the reaction mixture slowly to 25°C to 30°C followed by stirring,
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c) quenching the reaction mixture in an aqueous acid and extracting the product with water immiscible solvent and
d) separating the solvent layer and isolating crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane(III).
According to the process of the invention, crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) is purified by the process comprising steps of:
a) continuously charging the crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane to a short path distillation assembly and separating chlorobenzene from the product;
b) continuously charging the obtained product to short path distillation and separating 4-(4-chlorophenyl)-1 -acetyl-cyclohexane distillate;
c) stirring the obtained distillate with organic solvent and
d) isolating the off-white solid of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III).

o (ni)
According to an aspect of the present invention, oxidation of pure 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) comprises:
(a) dissolving compound (III) in organic solvent;
(b) adding sodium hypobromite solution at low temperature;
(c) adjusting pH of the reaction mixture to 2-4 using acid and
(d) isolating the off white solid of crude 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV).
According to another aspect of the present invention, crude 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV) is purified by the process comprising the steps of:
a) dissolving crude 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV) in polar solvent at elevated temperature ;
b) charging activated charcoal to the above solution and filtering the hot clear solution;
c) cooling the solution to ambient temperature;
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d) precipitating out the pure compound (IV) by adding water and
e) isolating the pure compound (IV) by filtration.

According to a further aspect of the invention, 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) is prepared by the process comprising:
a) charging compound (IV) to mixture of polar solvents and heating;
b) charging sequentially 2-chloro-l,4-naphthoquinone (V), water and silver nitrate to reaction mass at elevated temperature;

c) adding the aqueous solution of ammonium persulfate at elevated temperature;
d) cooling the reaction mass and separating the semi solid mass;
e) dissolving the semi solid mass in water immiscible solvent and filtering to obtain the residue;
1) concentrating the filtrate to obtain residue and
g) slurring the obtained residue with mixture of organic solvent to isolate the crude solid of compound (VI).

The process of hydrolyzing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphtho-quinone (VI) to produce crude solid of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone (I) comprising the steps of i
a) charging 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphtho-quinone(VI) to polar
protic solvent and heating at elevated temperature;
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b) adding alkali metal hydroxide solution to the obtained solution and refluxing;
c) cooling the reaction mass and adjusting pH to 2-3 using an acid and
d) isolating the crude solid of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-
naphthoquinone (I)
,ci


o (I)

OH

According to a further aspect of the present invention, there is provided a process for preparation of substantially pure 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphtho-quinone comprising the steps of:
a) dissolving crude Atovaquone (I) in an ethereal solvent at reflux temperature;
c) filtering the hot clear solution and cooling the filtrate to lower temperature to precipitate the yellow solid;
d) redissolving the obtained wet yellow solid in an ethereal solvent at reflux temperature;
e) filtering the hot clear solution and cooling to lower temperature and
f) isolating substantially pure Atovaquone.
The lewis acid catalyst is selected from aluminum chloride, zinc chloride, ferric chloride, preferably aluminum chloride used.
Preferably, chlorobenzene is used as reagent for arylation and solvent medium for Friedel-Carft acylation.
The organic solvent is selected from the group comprising water immiscible solvent, ethereal solvent, polar solvent and mixtures thereof.
The water immiscible solvent is selected from the group comprising an aliphatic hydrocarbon such as n-hexane, n-pentane, cyclohexane, an aromatic hydrocarbon such as chlorobenzene, a halogenated hydrocarbon , an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, an ester such as ethyl acetate and mixtures thereof.
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The halogenated hydrocarbon solvent is selected from chloroform, methylene dichloride
(MDC), ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-ethylenetrichloride and mixtures
thereof.
The ethereal solvent is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether,
petroleum ether, tetrahydrofuran, 1,4-dioxane and mixtures thereof.
The polar solvent is selected from a dipolar aprotic solvent, a polar protic solvent, an etheral
solvent and mixtures thereof.
The dipolar aprotic solvent is selected from acetonitrile, acetone, dimethylforaminde (DMF),
dimethylacetamide (DMA), N-methylacetamide, N-methylforamide, N,N-
dimethylprrrolidinone, N,N-dimethylpropionamide, dimethylsufoxide, sulfolane and mixtures
thereof.
The polar protic solvent is selected from C1-10 alcohols such as methanol, ethanol, isopropanol,
n-propanol, n-butanol, water and mixtures thereof.
The acid is selected from organic acid and mineral acid. An mineral acid is selected from
hydrochloric acid and sulfuric acid and the organic acid is selected from acetic acid and formic
acid. An aqueous acid is 10% to 50 % solution of mineral acid such as hydrochloric acid and
sulfuric acid and organic acid such as acetic acid and formic acid preferably 50 %
hydrochloric acid.
The alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, calcium
hydroxide and cesium hydroxide.
The term used herein "extremely lower temperature" refers to the temperature ranges from
- 40°C to -5°C.
The term used herein " lower temperature" refers to the temperature ranges from 0°C to 25°C.
According to the preferred embodiment of the present invention, mixture of cyclohexene and acetylchloride is added dropwise to mixture of chlorobenzene and lewis acid at extremely low temperature, preferably about -35°C to -20°C. The temperature is then increased slowly up to 25°C to 30°C and stirred for about 2 to 3 hour to remove hydrochloric acid gas. The reaction mixture is then quenched with chilled acidic solution and extracted with water immiscible solvent, preferably methylene chloride. The separated organic layer is distilled under reduced pressure to provide crude oily mass of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III).
Crude oily mass of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) contains about 25 to 35 % of
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chlorobenzene, which is then removed from the product either by azeotropic distillation with water at 70°C to 100°C under vacuum or passing through short path distillation assembly at 80°C to 135 °C under 1 mm to 10 Hg mm of reduced pressure vacuum. Oily mass of 4-(4-chlorophenyl)-l-acetyl-cyclohexane free from chlorobenzene is purified by subjecting to short path distillation and distillate having a boiling point from 130°C to 190 °C is collected under 0.001 mm to 5 mm Hg reduced pressure vacuum. The distillate of compound (III) thus collected is stirred with organic solvent, preferably n-hexane or petroleum ether at -15°C to -5°C for 1 hour to provide white solid of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III). The purity of solid product (III) is >98 % by HPLC.
Pure 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) thus obtained is converted to 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) by oxidation reaction whereby 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) is dissolved in organic solvent preferably 1,4-dioxane. Further aqueous sodium hypobromite solution is added to the reaction mixture at 15°C to 20°C and the reaction mixture is maintained at ambient temperature for 4-6 hours and the pH is adjusted to 3 to 4 using aqueous acid solution, preferably acetic acid. The crude compound of (IV) is filtered.
Crude 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV) is purified by dissolving in polar solvent, preferably DMF at about 55°C to 65°C. The hot solution is then treated with activated charcoal and filtered followed by cooling to 15°C to 35°C. Anti solvent added is preferably water to precipitate pure 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV), which is filtered, washed and dried at about 65°C to 70CC. The purity of solid product (IV) is >98 % by HPLC.
Pure 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) is stirred in a single or mixture of polar organic solvents preferably mixture of acetonitrile and sulfolane at a temperature of about 50°C to 65°C and 2-chloro-l,4-naphthoquinone, water and silver nitrate are added respectively at a temperature of about 50°C to 55°C to the above solution. Ammonium persulfate solution is added dropwise at 65°C to 80°C. The reaction mixture is further stirred for about 3-4 hours, cooled and the solvent is decanted from the reaction mass. The sticky mass is then dissolved in a water immiscible solvent in order to filter out inorganic impurity. Clear filtrate thus collected is then distilled off completely to provide semisolid mass which is stirred with mixture of
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organic solvent preferably MDC and acetonitrile to yield compound of formula VI. Further the product isolated by filtration and dried at 600C-70°C.
In a preferred embodiment of the present invention, the mixture of polar solvents comprises 1.0 -2.0 ml (w/v) acetonitrile, 2.0-6.0 ml (w/v)sulpholane and 4-8 ml (w/v) water per gram of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV). Preferred ratio of acetonitrile: sulfolane : water with respect to (IV) is 1.7 : 3.2 : 5.0 volume of solvent is half as mentioned in prior art. Preferably, the solution of ammonium persulfate is added to the reaction mass within 45-90 min. at 70°C to 85°C to get higher yield and formation trans Atovaquone. The compound 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone of formula (VI) is then heated in polar protic solvent, preferably methanol at 50 °C. An aqueous solution of alkali metal hydroxide, preferably potassium hydroxide is added to reaction mixture and reflux for 3 - 4 hrs. The reaction mixture is then cooled to 10°C to 20°C and adjusting 2-5 pH using acid, preferably hydrochloric acid. The crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone (I) (Atovaquone) is then isolated by filtration which is mixture of trans and cis isomer, having up to 75 % trans isomer, most preferably 50 to 75 %
Crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone (I) (Atovaquone) thus obtained is dissolved in an ethereal organic solvent, preferably 1,4-dioxane at 75 °C to 90 °C. The hot solution is then filtered and cooled to 15 to 25°C. The wet cake of purified Atovaquone thus obtained is further dissolved in ethereal organic solvent, preferably 1,4-dioxane at 75°C to 90 °C. The hot solution is then filtered, allowed to cool at 15 to 25°C and filtered solid material to obtain substantially pure Atovaquone.
According to the present invention, the obtained substantially pure Atovaquone is Form III characterized by having peaks at the following diffraction angles in its powder X-ray diffraction pattern,7.21, 9.85, 14.98,18.78,19.40 and 22.92 ± 0.2°.
The term 'substantially pure' refers to trans-isomer of Atovaquone of formula (I), thus obtained by the process as described in the present invention, is having less than 0.2 % of cis isomer. Preferably, trans isomer having its cis-isomer content 0.05 %.
The particle size d9o of the compound of formula (I) obtained by the process as described herein is in the range of 20-100^ and most preferably 25-45m. After micronisation d90 is in the range
15

of 0.3 - 20|a and most preferably 3 - 15m
The present invention also provides processes for preparing Atovaquone Form III with high purity.
When crude Atovaquone is dissolved in 1,4-dioxane at elevated temperature and the obtained clear solution was cooled slowly to 20°C, it is observed that there is an exotherm of 3°C at temperature of 37°C during the gradual cooling process. At this temperature sudden crystallization is observed and the whole solution is turned into a highly viscous unstirrable mass. The sudden precipitation is the reason for the formation of highly viscous mass.. This formation of highly viscous material makes the process disadvantageous not suitable for large scale production.
According to the present invention, solution of crude Atovaquone in ethereal solvent is is heated for 10-30 minutes to ensure complete dissolution of the solid and to obtain a clear solution. The hot solution is then allowed to cool to 40 to 60°C. At this temperature the Form III seed particles are added to the solution to obtain a free flowing solution, which is cooled to obtain Atovaquone Form III. Thus the present invention provides a method to prepare polymorphic form III of Atovaquone which involves optimized crystallization temperature, a key step in the process thereby avoiding formation of highly viscous mass. The improved method by optimizing the reaction conditions according to the invention, for preparation of the solid-state Atovaquone Form III is advantageous and industrially feasible as it is easy to handle during large scale production.
According to the invention process for preparation of substantially pure Atovaquone Form III comprises the following steps ;
a) dissolving crude Atovaquone (I) in an ethereal solvent at elevated temperature;
b) filtering the hot clear solution and cooling the filtrate to lower temperature to precipitate the yellow solid;
c) redissolving the obtained wet yellow solid in an ethereal solvent at elevated temperature;
d) filtering the hot clear solution and and adding seeds of polymorphic Form III at an elevated temp;
e) stirring the solution for several hours and isolating substantially pure polymorph of Atovaquone Form III and cooling to lower temperature.
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Ethereal solvents are selected from the group as described above, preferably 1,4-dioxane. The
elevated temperature is in the range of 40°C and 90°C, preferably 85°C. The cooling
temperature of the solution is in the range of 40°C to 60°C, preferably 20°C.
The seeding is carried out at the temperature range of 40°C to 60°C, preferably 48-55°C.
The seeded solution is stirred for 6-12 hrs at the same temperature preferably 6 hrs and dried at
temperature range of 50°C to 90°C, preferably at 65°C.
Preferably, crude Atovaquone is dissolved in 1,4-dioxane at 85 °C. The hot solution is then filtered and cooled to 20°C. The wet cake of purified Atovaquone thus obtained is further dissolved in 1,4-dioxane at 85 °C. The hot solution is allowed to cool to 48°C for 1 hr. When the temperature is reached at 48°C, the hot solution is seeded with Form III crystals and the solution is stirred for 6 hrs at the same temperature. The separated solids is isolated by filtration at same temperature and dried at 65 °C hrs to get substantially pure Form III of Atovaquone with HPLC purity of 99.80%.
According to another aspect of the invention, process for preparation of substantially pure Form III of Atovaquone comprises;
a) dissolving crude Atovaquone (I) in an ethereal solvent at an elevated temp ;
b) filtering the clear solution and cooling the filtrate to precipitate the yellow solid and
c) isolating substantially pure Atovaquone Form III.
Ethereal solvents are selected from the group as described above, preferably 1,4-dioxane. The elevated temperature is in the range of about 45°C and about 90°C, preferably 85°C The cooling temperature of the solution is in the range of 15°C to 60°C, preferably 20°C.
Preferably, crude Atovaquone is dissolved in 1,4-dioxane at 85 °C and maintaining the solution at the same temperature for 10 minutes. The hot solution is then slowly cooled to 20°C and filtered to obtain substantially pure Atovaquone Form III.
According to another aspect of the invention provides process for preparation of Atovaquone Form III which comprises the following steps ;
a) dissolving crude Atovaquone (I) in an ethereal solvent at an elevated temperature ;
b) cooling the solution obtained and adding seeds of polymorphic Form III at cooled temperature;
c) stirring the solution at same temperature for several hours and
d) isolating substantially pure Atovaquone Form III.
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Ethereal solvents are selected from the group as described above, preferably 1,4-dioxane. The elevated temperature is in the range of about 40°C and about 90°C, preferably 85°C. The seeding is carried out at the temperature range of 40°C to 60°C, preferably 48-55°C. The cooling temperature of the solution is in the range of 15°C to 60°C, preferably 48°C.
Preferably, crude Atovaquone is dissolved in 1,4-dioxane at 85°C and maintaining the solution at the same temperature for 10 minutes. The hot solution is allowed to cool to 48°C for 1 hr. When the temperature is reached at 48° C, the hot solution is seeded with Form III crystals and the solution is stirred for 4-6 hrs at the same temperature. The separated solids is isolated by filtration at same temperature and dried at 65°C to get substantially pure Atovaquone Form III.
According to the another aspect of the invention the process for preparation of substantially pure Atovaquone Form III comprises the steps of:
a) dissolving crude Atovaquone in aqueous ethereal solvent at an elevated temperature to form a clear solution;
b) cooling the solution followed by stirring at the same temperature for several hours and
c) isolating substantially pure polymorph of Atovaquone Form III.
The aqueous ethereal solvent used is preferably 1,4-dioxane. The water content in ethereal solvent is 10-50%, preferably 20-30%.
The elevated temperature is in the range of 45°C and 90°C, preferably 85°C. The cooling is carried out at temperature range of 20°C to 60°C, preferably 25 to 30°C. The cooled solution is stirred for 4-12 hrs at the same temperature preferably 6 hrs.
Preferably, crude Atovaquone is dissolved in 1,4-dioxane containing 20% water at temperature 85°C. The solution is maintained at the same temperature for 10 minutes. The hot solution is then allowed to cool to 30°C for 1 hr. The solution is further stirred for 6 hrs at the same temperature. The separated solid is isolated by filtration at same temperature and dried at 65°C to get substantially pure Form III with purity 99.81%.
X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Ka (l = 1.5406 A) radiation with scanning range between 4-50 0 at scanning speed of 2°/min. The X-ray powder diffraction diagram of Form III is shown in Figure 1. The substantially pure Atovaquone Form III as obtained by the
18

process described herein exhibits the following XRPD:

Pos. [°2Th.l Rel. Int. [%1
7.1679 35.14
9.8280 100.00
12.8452 2.22
14.3674 11.77
14.9585 50.30
17.2609 1.83
18.7586 75.93
19.3931 22.06
20.2373 19.65
20.8491 7.95
22.2076 7.89
22.9069 17.03
23.4711 18.45
24.5072 40.19
25.3627 4.07
25.7285 8.75
26.4587 24.05
27.0508 15.35
27.3982 6.86
27.9061 4.77
28.6885 7.95
30.7067 3.56
32.8628 4.55
33.6562 4.53
34.6429 4.51
35.4085 10.68
36.0005 3.80
37.8249 2.53
38.8678 2.74
39.6729 18.23
40.9921 6.10
41.8263 6.93
44.5894 23.53
45.3891 5.59
46.1711 4.82
46.6402 4.74
48.7425 3.55
49.0172 4.90
Thus, this improved process for preparing Atovaquone Form III is highly productive and commercially viable.
The single crystal x-ray diffraction data collected on Bruker SMART-APEX CCD diffractometer showed that substantially pure trans Atovaquone polymorphic form III prepared
19

according to the present invention is different from that of known Atovaquone (I) polymorphic Form I. Crystal structure of Atovaquone Form III and Form I are shown in figure 1 and 2. Table I shows a comparison of single crystal characteristics for Form I & Form III of Atovaquone.
Table l.Crystallographic data and structure refinement of Form I and Form III

Atovaquone Form I Form III
Crystal system Monoclinic Monoclinic
Space group P21/n P21/c
a 5.9258(3) A3 12.5143(14) A3
b 18.3607(10) A3 5.26143(6) A3
c 16.6369(9) A3 27.823(3) A3
a 90° 90°
P 97.206(1)° 92.581(2)°
Y 90° 90°
Volume 1795.83(17) A3 1830.1(4) A3
The present invention is illustrated in further detail with reference to the following non-limiting examples. Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way.
Example 1
Preparation of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III)
1350 gm of chlorobenzene and 972.5 gm of anhydrous aluminium chloride were stirred together at -35°C to -20°C for 30min. Mixture of cyclohexene (500 gm) and acetylchloride (425 gm) was added dropwise to above reaction mixture at -30°C to -20°C.The temperature of the reaction mixture was increased to 25°C to 30°C and stirred for 2-3 hours and further quenched in a mixture of 3.75 lit chilled water and 1.7 lit cone, hydrochloric acid. 1500 ml MDC was added and stirred for 1 hour, the organic layer separates out, 500 ml MDC was then added to aqueous layer and stirred for 30 min. The combined organic layer was washed with IN
20

sodium hydroxide (380 ml) and water, dried over anhydrous sodium sulphate and evaporated to dryness to get oily product. Oily product thus obtained was then subjected to short path distillation and the distillate having a boiling point in the range of 150°C to 175°C was collected under 0.02 mm Hg reduced pressure. 250 ml of the distillate fraction was stirred with 500 ml of n-hexane at -5 to -15 °C for 1 hour to obtain crystals of 4-(4-chlorophenyl)-l-acetyl-cyclohexane. The product was filtered, washed with chilled n-hexane and dried at 30°C to 35°C under reduce pressure , to give title compound ( 152.23 g, yield : 30.44 %, Purity: 99.3 %) as off white crystals.
Example 2
Preparation of 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV)
Bromine (83 ml) was added to a solution of sodium hydroxide (239 gm) in water (1600 ml) at 5°C to 10°C. 120 gm of 4-(4-chlorophenyl)-l-acetyl-cyclohexane was dissolved in 580 ml of 1,4-dioxane and cooled to 5°C to 10°C. Sodium hypobromite solution prepared above was added to the reaction mixture at a temperature below 20°C. The reaction mixture was stirred at ambient temperature for about 6 hours. Further sodium metabisulphite was added to destroy excess hypobromite, the reaction mixture was cooled and acidified with acetic acid to get the crude solid of 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid, which was then filtered and dried at 60°C to 65°C ( 148.9 g, yield : 97.9 %, Purity: 95.3 %) as off white crystals.
Example 3
Purification of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid
110 gm of crude 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV) was dissolved to 660 ml DMF at 55°C-65°C. 6 gm activated charcoal was then added, stirred for 30 min and filtered to obtain the clear filtrate. 660 ml of water was added to filtrate at 15 to 35 °C to precipitate the pure white solid. The solid was filtered, washed with chilled water and dried at 65 °C to 70°C (141.5 g, yield: 94.35 %, Purity: 98.5 %).
Example 4
Preparation of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l,4-naphthoquinone (VI)
A mixture pure 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (100 gm), acetonitrile (170 ml) and sulpholane (320ml) were stirred at 50°C to 55°C for 30 min. 75gm 2-chloro-l,4-naphtnoquinone (V), 500ml water and 18.8gm silver nitrate were added respectively at 50°C to 55°C. A solution of 240 gm ammonium persulfate in 480 ml water was prepared and added
21

dropwise to the reaction mixture at 75°C-80°C and stirred for 3 hours at 75°C to 80°C. The reaction mass was cooled to 30°C to 35°C and the separated solvent was decanted and 600 ml MDC was added to dissolve the sticky mass. The inorganic impurity was filtered off. The filtrate was collected and distilled off completely to yield semisolid mass. 100 ml MDC and 300 ml acetonitrile was added to the semi solid mass and stirred at 25°C to 35°C for 1 hour to provide light yellow solid, which was then filtered and washed with acetonitrile and then dried at 60 to 65 °C to get 111.5 g of the title compound (VI) (Yield : 78.8 % Purity: trans isomer : 47.69 % , cis isomer 48.32 %.
Example 5
Preparation of 2- [4-(4-chlorophenyl)-cyclohexyI] -3-hydroxy-l ,4-naphthoquinone
(Atovaquone)
75 gm of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l,4-naphthoquinone was added to 1500 ml methanol and heated to 50°C. To this a solution of 75 gm of potassium hydroxide in 150 ml water was added dropwise. The reaction mixture was refluxed for 4 hours and cooled to 15 °C and 112 ml. Concentrated HC1 acid was added drop wise to adjust pH 3 to 4 of the reaction mixture. The reaction mixture was stirred at 15 °C for 1 hour to yield light yellow solid, which was then filtered, washed with water and dried at 60°C to 65°C to get 107.6 g crude solid of Atovaquone. Yield : 97.5 %, Purity: trans isomer : 52. 22 % , cis isomer 45.01 %.
Example 6
Purification of 2- [4-(4-chlorophenyl)-cyclohexyl] -3-hydroxy-l ,4-naphthoquinone
(Atovaquone) (I).
56 gm of crude Atovaquone was dissolved in 280 ml of 1,4-dioxane at 85°C and stirred to obtain a clear solution. The hot solution was filtered and the filtrate was cooled to 20°C and filtered to get solid. The wet cake thus obtained was dissolved in 112 ml of 1,4-dioxane at 85 °C. The hot clear solution was filtered and the filtrate was slowly cooled to 40 °C to get the substantially pure Atovaquone which was filtered and dried at 75 °C to give 53.5 g of the title compound. Yield : 50.68 %, Purity: trans isomer : 99.82 % , cis isomer 0.06 %.
Example 7: Preparation of substantially pure Atovaquone Form III.
5 gm of crude Atovaquone was dissolved in 25 ml of 1,4-dioxane at 85°C and stirred to obtain a clear solution. The hot solution was filtered and cooled the filtrate to 20°C to precipitate out the solid. The wet cake thus obtained was dissolved in 10 ml of 1,4-dioxane at 85 °C. The hot
22

solution was allowed to cool to 48°C for 1 hr. When the temperature reached at 48°C, Atovaquone Form III seeds were added to the hot solution. The hot solution was cooled slowly to 40° for 6 hrs. The separated solids were isolated by filtration at same temperature. The solids were dried at 75 °C to get substantially pure Atovaquone Form III with purity 99.79% (yield 2.0 g).
Example 8
5 g crude Atovaquone was dissolved in 35 ml 1,4-dioxane at 85°C. The solution was maintained at the same temperature for 10 minutes. The hot clear solution was filtered and the filtrate was slowly cooled to 20 °C, stirred for 2-3 hrs to precipitate out yellow crystals. The resulting crystals were collected by filtration and dried at 75°C to get substantially pure Atovaquone Form III with purity 99.12% (yield 1.5 g)
Example 9
5 g crude Atovaquone was dissolved in 20 ml of 1,4-dioxane at 85°C. The solution was maintained at the same temperature for 10 minutes. The hot solution was allowed to cool to 48°C for 1 hr. When the temperature reached at 48°C, Form III seeds were added to the hot solution. The hot solution was cooled slowly to 40° for 6 hrs. The separated solids were isolated by filtration at same temperature. The solids were dried at 65°C to get substantially pure Form III with purity 99.54% (yield 2.0g).
Example 10
5 g crude Atovaquone was dissolved in 15 ml 1,4-dioxane containing 20% water at 85°C. The solution was maintained at the same temperature for 10 minutes. The hot solution was allowed to cool to 30°C for 1 hr. The solution was stirred for 6 hrs at the same temperature. The separated solids were isolated by filtration at same temperature. The solids were dried at 65°C, to get substantially pure Form III with purity 99.26% (yield 1.65g).
23

We claim,
1. Process for the preparation of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone) of formula (I) comprising the steps of: a) reacting cyclohexene with acetyl chloride in presence of lewis acid and chlorobenzene to obtain crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane(III);
o (m)
purifying crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) by continuous
short path distillation and isolating solid of compound (III);
oxidizing the compound (III) to get 4-(4-chlorophenyl)cyclohexane-l-carboxylic
acid (IV);
purifying the obtained 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV) using
polar solvent and isolating pure compound (IV);

e) condensing the pure compound (IV) in a mixture of polar solvents with 2-chloro-1,4-naphthoquinone (V) in presence of silver nitrate and ammonium persulfate to obtain 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI);
24

optionally purifying 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l,4-naphthoquinone (VI) from an organic solvent;
g) hydrolyzing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) in polar protic solvent in presence of aqueous alkali metal hydroxide to obtain crude 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone (I) at temperature 45°C to 65°C ; and
-CI

h) purifying 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-naphthoquinone (I) in an ethereal solvent to get substantially pure Atovaquone.
2. The process as claimed in claim 1, wherein preparation of 4-(4-chlorophenyl)-l-acetyl- cyclohexane (III) comprises:
a) adding acetyl chloride and cyclohexene (II) to a mixture of chlorobenzene and lewis acid at extremely low temperature range of - 40°C to -5°C;
b) raising the temperature of the reaction mixture slowly to 25°C to 30°C ;
c) quenching the reaction mixture in an aqueous acid and extracting the product with water immiscible solvent;
d) separating the organic layer from reaction mixture containing product and
e) isolating crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane by evaporating the solvent.
25

3. The process as claimed in claim 2, wherein lewis acid is selected from aluminum chloride, zinc chloride and ferric chloride, preferably anhydrous aluminum chloride.
4. The process as claimed in claim 2, wherein an aqueous acid is 10% to 50 % solution of mineral acid such as hydrochloric acid and sulfuric acid and organic acid such as acetic acid and formic acid preferably 50 % hydrochloric acid.
5. The process as claimed in claim 1, wherein purification of crude oil of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) comprises,

a) continuously charging the crude oil of 4-(4-chlorophenyl)-l -acetyl- cyclohexane (III) to a short path distillation assembly at 80°C to 125 °C under 1 mm to 10 Hg mm of reduced pressure vacuum for separating chlorobenzene from the product;
b) continuously charging the product obtained to short path distillation and separating distillate 4-(4-chlorophenyl)-l-acetyl-cyclohexane at 130°C to 190 °C under 0.001 mm to 5 mm Hg reduced pressure vacuum.
c) stirring the distillate obtained in organic solvent at low temperature range of -15°C to 5°C and
d) isolating the solid of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) with > 99.5 % purity.

6. The process as claimed in claim 1 wherein oxidation of 4-(4-chlorophenyl)-l-acetyl-cyclohexane (III) is carried out using sodium hypobromite solution at temperature of 10 -15°C in organic solvent to get crude compound (IV).
7. The process as claimed in claim 1, wherein purification of crude 4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (IV) comprises,

a) dissolving crude compound of formula (IV) in polar solvent at an elevated temperature of 55°C to 65°C;
b) charging activated charcoal to the obtained solution and filtering the hot clear solution and
c) cooling the filtrate at temperature 15°C to 35°C and isolating the pure compound (IV) by precipitating out by addition of water.
8. A process as claimed in claim 1, wherein preparation 2-[4-(4-chlorophenyl)-
cyclohexyl]-3-chloro-l, 4-naphthoquinone (VI) comprises,
a) charging pure compound (IV) to mixture of polar solvent and heating at temperature of 55°C to 65°C;
b) charging sequentially 2-chloro-l,4-naphthoquinone (V), water and silver nitrate
26

to the obtained reaction mass at elevated temperature of 50°C to 55°C;
c) raising the temperature of the obtained reaction mixture to 75°C to 80°C followed by addition of aqueous solution of ammonium persulfate;
d) cooling the reaction mass to separate the semi solid mass;
e) dissolving the semi solid mass in water immiscible solvent and filtering;
f) concentrating the filtrate and treating the residue with a mixture of organic solvents and
g) isolating the crude solid of compound (VI).

9. The process as claimed in claim 1, 5, 6 and 8, wherein organic solvent is selected from water immiscible solvent, ethereal solvent, polar solvent, and mixtures thereof.
10. The process as claimed in claim 1, 2 and 8, wherein water immiscible solvent is selected from the group comprising an aliphatic hydrocarbon such as n-hexane, n-pentane, cyclohexane, an aromatic hydrocarbon such as chlorobenzene, a halogenated hydrocarbon such as chloroform, methylene dichloride (MDC), ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-ethylenetrichloride, an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether , an ester such as ethyl acetate and mixtures thereof.
11. The process as claimed in claim 1,7,8 and 9, wherein polar solvent is selected from dipolar aprotic solvent, polar protic solvent and mixtures thereof.
12. The process as claimed in claim 11, wherein dipolar aprotic solvent is selected from acetonitrile, acetone, dimethylforaminde (DMF), dimethylacetamide (DMAC), N-methylacetamide, N-methylforamide, N,N-dimethylprrrolidinone, N,N-dimethylpropionamide, dimethylsufoxide, sulfolane and mixtures thereof.
13. The process as claimed in claim 11, wherein the polar protic solvent is selected from Ci-io alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol, water and mixtures thereof.
14. The process as claimed in claim 8, wherein polar solvents is the mixture 1.0 -2.0 ml (w/v) acetonitrile, 2.0 to 6.0 ml (w/v)sulpholane and 4.0 to 8.0 ml (w/v) water per gram of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid (IV).
15. The process as claimed in claim 1, wherein hydrolyzing 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphtho-quinone (VI) to produce crude solid of 2-[4-(4-chlorophenyl)-cyclohexyl] -3 -hydroxy-1,4-naphthoquinone (I) comprising the steps of:
a) charging 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-l, 4-naphtho-quinone(VI) to
27

polar protic solvent and heating at elevated temperature;
b) adding alkali metal hydroxide solution to the obtained solution and refluxing;
c) cooling the reaction mass and adjusting pH to 2-3 using acid and
d) isolating the crude solid of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-l,4-
naphthoquinone (I)
16. The process as claimed in claim 1 and 15, wherein alkali metal hydroxide used for hydrolysis reaction is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, preferably is potassium hydroxide .
17. The process as claimed in claim 15, wherein acid is selected from mineral acid such as hydrochloric acid and sulfuric acid and the organic acid such as acetic acid and formic acid, preferably acetic acid.
18. The process as claimed in claim 1, wherein purification of crude 2-[4-(4-chlorophenyl)-cyclohexyl] -3 -hydroxy-1,4-naphthoquinone (I), comprises;

a) dissolving crude compound (I) in an ethereal solvent at reflux temperature or 65°C to 85°C;
b) filtering the obtained hot clear solution and cooling to lower temperature of 20°C to 25°C to precipitate out the solid;
c) filtering the solid obtained and redissolving in ethereal solvent at reflux temperature;
d) filtering the hot clear solution and isolating the substantially pure Atovaquone from the filtrate by cooling at lower temperature of 20°C to 25°C.

19. The process as claimed in claim 1, 9 and 18, wherein ethereal solvent is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane.
20. The process as claimed in claim 18, wherein the isolated substantially pure Atovaquone is pure trans-isomer of Atovaquone of formula (I) having < 0.2 % of cis-isomer, preferably < 0.05%
21. Pure Atovaquone prepared by the process as claimed in claim 1 to 19 is characterized by having peaks at the following diffraction angles in its powder X-ray diffraction pattern,7.21, 9.85,14.98,18.78,19.40 and 22.92 ± 0.2°.
22. Pure Atovaquone as claimed in claim 21 is having particle size d9o in the range of 20 to 100m., preferably 25 to 5(i and in the range of 0.3 to 20m.
23. The process for preparing pure Atovaquone Form III comprises,
a) dissolving crude Atovaquone (I) in an ethereal solvent at an elevated temperature
28

of 40°C to 90°C;
b) filtering the hot clear solution and cooling the filtrate at temperature 40°C to 90° to precipitate the yellow solid;
c) redissolving the obtained wet yellow solid in an ethereal solvent at an elevated temperature ranging from 40°C to 90°C;
d) filtering the hot clear solution and adding seeds of polymorphic Form III at an elevated temperature;
e) stirring the solution for several hours and isolating substantially pure polymorph of Atovaquone Form III.

24. The process as claimed in claim 23, wherein seeding is carried out at temperature ranges from 40°C to 60°C;
25. The process for preparing substantially pure Atovaquone Form III comprises;

a) dissolving crude Atovaquone (I) in an ethereal solvent at an elevated temperature of 45°C to 90°C;
b) cooling the filtrate at temperature of 15°C to 60°C; to precipitate the yellow solid;
c) isolating substantially pure Atovaquone Form III.
26. The process for preparing substantially pure Atovaquone Form III comprises;
a) dissolving crude Atovaquone (I) in a ethereal solvent at an elevated temperature of about 45 °C to 90°C to form a clear solution;
b) cooling the solution obtained followed by addition of seeds of polymorphic Atovaquone Form III;
c) stirring the obtained solution for several hours and
d) isolating substantially pure Atovaquone Form HI.

27. The process as claimed in claim 26, wherein the cooling and seeding is carried out at temperature in the range of 40°C to 60°C.
28. The process for preparing pure Atovaquone Form III comprises,

a) dissolving crude Atovaquone (I) in a aqueous ethereal solvent at an elevated temperature of 45°C to 90°C to form a clear solution;
b) cooling the solution and stirring for several hours at the same temperature and
c) isolating the pure Atovaquone Form III.

29. The process as claimed in claim 23, 25 , 26 and 28 , wherein the ethereal solvent is 1,4-dioxane.
30. Atovaquone Form III obtained by the process as claimed in claim 23 or 25 or 26 or 28 is
29

having the particle size d90 in the range of 40 to l00m, 31. The process for preparation of substantially pure Atovaquone and polymorph Form III thereof substantially as described herein with reference to the foregoing examples 1 to

30

Abstract:
The present invention relates to process for preparation of 2-[4-(4-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone commonly known as Atovaquone and intermediates thereof. More particularly, the present invention relates to a process for preparation of substantially pure Atovaquone and a process for preparation of substantially pure Atovaquone Form HI.