CLIAMS:1) A process for preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4- naphthoquinone i.e. Atovaquone [I] comprising of-
i) Reaction between organometallic reagent of 2-bromodimethoxy naphthalene [II] with 4-(4-chlorophenyl)cyclohexanone [III] to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxy -naphthalen-2-yl)cyclohexanol (V) in organic solvent;
ii) Dehydration of 4-(4-chlorophenyl)-1-(1,4-dimethoxy-naphthalen-2-yl) -cyclohexanol (V) in presence of bronsted acid to obtain 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) in toluene at 60 0C;
iii) Hydrogenation of 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) with noble metal catalyst to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) in ethyl acetate at 250C;
iv) Oxidation of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) with ceric ammonium nitrate to obtain 2-(4-(4-chlorophenyl)cyclohexyl) -naphthalene-1,4-dione (VIII) in acetonitrile at 25 0C;
v) Epoxidation of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII) using oxidizing agent to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-naphthalene-1,4-dione [IX] in presence of inorganic base.
vi) Acid catalyzed hydrolysis of 2-(4-(4-chlorophenyl)cyclohexyl)-naphthalene-1,4-dione [IX] to give Atovaquone [I].

2) The process according to claim 1 step i) wherein the organic solvent used is tetrahydrofuran, methyl-tetrahydrofuran, heptane or mixture thereof, preferably tetrahydrofuran.
3) The process according to claim 1 step ii) wherein the acid used is p–toluene sulfonic acid.
4) The process according to claim 1 step iii), wherein the hydrogenation is carried out using noble metal catalyst such as palladium on carbon, palladium hydroxide on carbon, platinum oxide and platinum on carbon preferably palladium on carbon.
5) The process according to claim 1 step iii) wherein hydrogenation is carried out with hydrogen pressure 3-5 kg/cm2.
6) The process according to claim 1 step vi) wherein epoxidation is carried out using hydrogen peroxide.
7) The process according to claim 1 step v) wherein inorganic base used for epoxidation is sodium bicarbonate.
8) The process according to claim 1 step vi) wherein hydrolysis is carried out using acid such as hydrochloric acid, nitric acid or sulfuric acid preferably sulfuric acid.
9) A process for preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4- naphthoquinone i.e. Atovaquone [I] comprising of
i) Reaction between organometallic reagent of 2-bromodimethoxy naphthalene [II] with 4-(4-chlorophenyl)cyclohexanone [III] to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxy -naphthalen-2-yl)cyclohexanol (V) in organic solvent;
ii) Dehydration of 4-(4-chlorophenyl)-1-(1,4-dimethoxy -naphthalen-2-yl)cyclohexanol (V) in presence of acid to obtain 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) in toluene at 60 0C;
iii) Hydrogenation of 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) with noble metal catalyst to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) in ethyl acetate at 250C;
iv) Bromination of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) with bromine in organic solvent to give 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X);
v) oxidation of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxy -naphthalene (X) with ceric ammonium nitrate in organic solvent to obtain 2-bromo-3-(4-(4-chlorophenyl)-cyclohexyl)naphthalene-1,4(4aH,8aH)-dione (XI);
vi) hydrolysis of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-naphthalene-1,4(4aH,8aH)-dione (XI) using inorganic base to give cis/trans mixture of Atovaquone; and
vii) Isomerization from cis/trans mixture of atovaquone to atovaquone [I] in presence of sulfuric acid.
10) The process according to claim 1 step i) wherein the organic solvent used is tetrahydrofuran, methyl-tetrahydrofuran, heptane or mixture thereof, preferably tetrahydrofuran.
11) The process according to claim 1 step ii) wherein the acid used is p–toluene sulfonic acid.
12) The process according to claim 1 step iii), wherein the hydrogenation is carried out using noble metal catalyst such as palladium on carbon, palladium hydroxide on carbon, platinum oxide and platinum on carbon preferably palladium on carbon.
13) The process according to claim 1 step iii) wherein hydrogenation is carried out with hydrogen pressure 3-5 kg/cm2.
14) The process according to claim 9 step iv) wherein the solvent used for bromination is dichloromethane or chloroform preferably dichloromethane.
15) The process according to claim 9 step v) wherein the solvent used for oxidation is dichloromethane, chloroform, carbon tetrachloride, preferably dichloromethane.
16) The process according to claim 9 step vi) wherein hydrolysis is carried out using base such as potassium hydroxide or sodium hydroxide preferably potassium hydroxide.
17) The 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol compound (V).
18) The 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene compound (VI).
19) The 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene compound (VII).
20) The 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene compound (X).
21) Use of compound (V) or compound (VI) or compound (VII) or compound (X) for preparation of atovaquone [I]. ,TagSPECI:Field of the Invention:
The invention relates to a novel process for preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone i.e. Atovaquone [I].
Background of the Invention:
2-[Trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, as disclosed in US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria, toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US 5206268, US 5856362 and US 5567738, respectively. The mechanism of action for Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome bc1 complex, which is linked to pyrimidine biosynthesis (Tetrahedron Letters, 1998, 39 7629).

[I]
There are only a few reports available for the synthesis of Atovaquone employing various synthetic alternatives essentially based on Hunsdiecker decarboxylative condensation, which proceeds through a radical mechanism. However, the overall yield of the desired product in almost all the reported processes is exceedingly poor i.e. economically far away from attractive one.
Our PCT application WO/2012/153162 entitled “Novel method for synthesis of Atovaquone”, describes process for synthesis of Atovaquone, as shown in scheme 1, disclosers of which, including prior art are incorporated herein by reference.
Scheme I
The present inventors have developed an inventive, significantly cost effective, operation friendly process for preparation of the title compound.

Objects of the Invention:
Thus an object of this invention is to provide a novel cost effective and efficient process for the synthesis of Atovaquone [I].
Another object of the present invention is synthesis of the novel compound 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) through organometallic reagent obtained from 2-bromo-1,4-dimethoxynaphthalene (II) with 4-(4-chlorophenyl)cyclohexanone (III) and its further conversion to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) through ortho lithiation reactions between 1,4-dimethoxynaphthalene (IV) and 4-(4-chlorophenyl)cyclohexanone, (III), which is further converted to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) from 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) through dehydration in presence of bronsted or lewis acid, which is further converted of to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) from 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) through hydrogenation in presence of noble metal hydrogenation catalysts, which is further converted to Atovaquone [I].
Yet another object of the present invention is synthesis of the compound 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII) from 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) through oxidation and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the compound 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X) from 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) through bromination and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the compound 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4(4aH,8aH)-dione (XI) from 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X) through oxidation and further conversion of it to Atovaquone [I].
Summary of Invention:
1) In the present invention, 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, i.e. Atovaquone [I] was obtained through a novel, significantly cost effective and industrial feasible process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions as depicted in Figure I.
Route I: A process for preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, i.e. Atovaquone [I] comprising the steps of-
a) condensing of 2-bromo-1,4-dimethoxynaphthalene (II) with 4-(4-chlorophenyl) -cyclohexanone (III) in presence of n-butyl lithium in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);
Or
a) reaction between Grignard regent of 2-bromo-1,4-dimethoxynaphthalene (II) and 4-(4 chlorophenyl)cyclohexanone (III) in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);
Or
a) Ortho lithiation of 1,4-dimethoxynaphthalene (IV) and then condensation with 4-(4 chlorophenyl)cyclohexanone (III) in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);

b) dehydration of 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) in organic solvent and in presence of bronsted or lewis acid such as p–toluene sulfonic acid to 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VI);

c) hydrogenation of 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) with noble metal hydrogenation catalysts in presence of hydrogen atmosphere to obtain cis/trans mixture of 2-(4-(4-chlorophenyl) -cyclohexyl)-1,4-dimethoxynaphthalene (VII);
d) oxidation of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) with ceric ammonium nitrate in organic solvent to obtain 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII);

e) base catalyzed epoxidation of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII) to 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (IX) with hydrogen peroxide;

f) acid catalyzed hydrolysis of 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (IX) to obtain 2-[trans-4-(4'-chlorophenyl) -cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I].

Route II: A process for preparation of Compound [I] comprising the steps of-
a) condensing 2-bromo-1,4-dimethoxynaphthalene with 4-(4 condensing of 2-bromo-1,4-dimethoxynaphthalene (II) with 4-(4 chlorophenyl)cyclohexanone (III) in presence of n-butyl lithium in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);
Or
a) reaction between Grignard regent of 2-bromo-1,4-dimethoxynaphthalene (II) and 4-(4 chlorophenyl)cyclohexanone (III) in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);
Or
a) Ortho lithiation of 1,4-dimethoxynaphthalene (IV) and then condensation with 4-(4 chlorophenyl)cyclohexanone (III) in organic solvent to obtain 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V);

b) dehydration of 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) in organic solvent and in presence of bronsted or lewis acid such as pTSA to 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VI);

c) hydrogenation of 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI) with noble metal hydrogenation catalysts in presence of hydrogen atmosphere to obtain cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII);

d) Bromination of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII) with bromine in organic solvent to obtain 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X);

e) Oxidation of 2--bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X) to 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XI) in presence with ceric ammonium nitrate in organic solvent;

f) Base catalyzed hydrolysis of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XI) to obtain 2-[cis/trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I];

g) Acid catalyzed quantitative isomerization of a mixture of 2-cis & 2-trans-4-(4'-chlorophenyl)cyclohexyl-3-hydroxy-1,4-naphthoquinone to the trans isomer i.e. Atovaquone [I].

Detail description:
The present invention relates to process for preparation of Atovaquone [I] as described in the scheme of reactions in Figure I.
Strategy was to prepare the ortho-metalated intermediate of 1,4-dimethoxynaphthalene and react with the desired electrophile i.e. 4-(4-chlorophenyl)cyclohexanone (III) to build the skeleton of compound (I), which on subsequent chemical transformations was converted to compound (I).

The reaction of an alkyllithium compound with an arene bearing a "directed metalation group" (DMG) leads to an ortho-metalated intermediate and further, its reaction with variety of electrophiles are well documented in the literature (J. Am. Chem. Soc. 1998, 120, 421-422; Chem. Rev. 1990, 90, 879-933).

2-Lithiated-1, 4-dimethoxynaphthalene (ortho-lithiated-1,4-dimethoxynaphthalene) was produced either from compound (IV) or compound (II), as per reported procedures (Tetrahedron, 1998, 54, 5363-5374; as well as (J. Org. Chem, 2011, 76, 8082-8087; J. Org. Chem 1986, 51, 350-358; J. Org. Chem 2010, 75, 8701-8704).

Thus, ortho-metalated intermediate of 1,4-dimethoxynaphthalene was reacted with 4-(4-chlorophenyl)cyclohexanone (III) in organic solvent at -700C to obtain the 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) in 66-70% yield.

Compound (V) was also obtained through reaction between Grignard reagents prepared from compound (II) and compound (III).

Organic solvent used for obtaining organometallic reagent for compound (II) were selected from THF, 2-methyl THF or mixture of solvent such as n-heptane/THF.
Dehydration of Compound (V) in presence of Bronsted or Lewis acid in an organic solvent gave compound (VI) in excellent yield.

Dehydration employing Bronsted acid i.e. p- toluenesulfonic acid in toluene at 60 0C was gave the compound (VI) in quantitative yield. Compound (VI) was further crystallized from acetonitrile to obtain white crystalline material.

Hydrogenation of compound (VI) using noble metal hydrogenation catalyst such as palladium on carbon, palladium hydroxide on carbon, platinum oxide and platinum on carbon in organic solvent such as ethyl acetate, acetone preferably ethyl acetate gave cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene) (VII) at 25 0C in quantitative yield, the ratio of two geometric isomer is approximately equal.

Cis and trans isomers of compound (VIII) were separated through selective crystallization as it was observed that in acetonitrile, one isomer was more soluble that the other isomer and after recrystallizations in actonitrile, one isomer was obtained in the pure form. Single crystal was obtained from the pure isomer and structure was assigned through a X-ray single crystal analysis and it was observed that the pure compound is trans-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene). It show the crystals are monoclinic (a = 9.4918Å, b=10.9691Å, c=20.362Å; a=90.000, b=110.130, g=90.000), having Z value 4.
The ORTEP diagram of trans-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene) (VII), where bulky groups in 1, 4 position of the cyclohexane ring have equatorial conformation is shown in figure 1.
DSC melting point for trans-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene)
(VII) is 175.4 0C.


Other isomer of compound (VII) i.e. cis isomer was also obtained from mother liquor after crystallization from methanol.

DSC melting point for cis-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene) (VII) is 79.2 0C.
Optionally separation of cis and trans isomer of compound (VII) can be achieved through fractional crystallization. By employing chemistry described hereinafter synthesis of individual cis and trans isomer of compound (I) can be done.

Synthesis of corresponding quinone derivatives from substituted 1,4-dimethoxynaphthalene is known in literature by oxidation with ceric ammonium nitrate (CAN) (J. Org. Chem., 1976, 41, 3627–3629). Oxidation of mixture of cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene) (VII) with ceric ammonium nitrate in organic solvent at 0-25oC gave the mixture of cis/trans-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII) in 95% yield.

cis/trans-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII) was crystalized from a mixture dichloromethane/cyclohexane, having the DSC melting point of 137.7 °C.
Organic solvent used for oxidation reaction use for oxidation reaction was selected from THF, acetonitrile, dioxane; preferably acetonitrile.

CAN oxidation reaction was carried out at temperature range from 0-25 0C, preferably at 25oC.

Compound (VIII) was subsequently converted to cis/trans-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (IX) in presence of 30% aqueous hydrogen peroxide and base such as sodium carbonate, having the DSC melting point 155.0 oC.
Compound (IX) on hydrolysis with concentrated sulfuric acid gave Atovaquone (I), which was crystalized from acetonitrile to obtain pure compound (I) in 70% isolated yield having HPLC purity 99%. Retention time of compound (I) is identical with authentic sample and has identical spectral data as reported in literature.
Route –II:

Compound (VII) was synthesized as described in Route-I.

Bromination of compound (VII) with bromine in chlorinated organic solvent at 0 -10 oC gave the 2--bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X).

Chlorinated organic solvent used for bromination reaction was selected from dichloromethane, Chloroform, carbon tetrachloride; preferably dichloromethane.

Oxidation of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X) with ceric ammonium nitrate in organic solvent at 0-25oC gave the 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XI).

Organic solvent used for oxidation reaction was selected from THF, acetonitrile, dioxane; preferably acetonitrile.

Hydrolysis of compound (XI) with 20% solution of potassium hydroxide in mixture of methanol/tetrahydrofuran at 250C gave crude compound (I), which was further isomerized to trans isomer in presence of concentrated sulphuric acid at 25oC to obtain compound (I).

Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 12.

Example 1: Synthesis of 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V)
A solution of compound (II) (30 g) in anhydrous tetrahydrofuran (300 mL) was cooled to -70 0C and then slowly added solution of n-butyl lithium (62 mL, 123.5 mmol) in cyclohexane over a period of 30 min. After which reaction mixture was stirred for 2 h at -45 0C and again cooled to -70 0C. A solution of compound (III) (23.4 g, 112.3 mmol) in anhydrous tetrahydrofuran (240 mL) was slowly added to above reaction mixture at -70 0C and further stir the reaction mass for 3 h at -500C. The reaction mass was stirred for 1 h at -50 ̊C and then reaction was quenched with 10 % ammonium chloride solution (100 mL) at 0 ̊C, stripped off, volatile matter under reduced pressure. Crude product was extracted with dichloromethane (3×200 mL). Organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude product as semisolid (49.5 g). HPLC analysis shows that crude product is mixture of geometric isomer and overall conversion to compound (V) was 70 %. Separation of geometric isomer through selective crystallization in methanol was achieved.
FTIR (KBr): 3460, 3005, 2947, 2935, 1625, 1593, 1507, 1493, 1459, 1359, 1334, 1260, 1108, 1088, 1039, 1013, 982, 832, 766 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.81-1.84(m, 2H), 2.12-2.24 (m, 6H), 2.63-2.66 (m, 1H), 4.03 (s, 3H), 4.04 (s, 3H), 4.97 (bs, 1H), 6.81 (s, 1H), 7.26-7.32 (m, 4H), 7.49 (t, 1H), 7.57 (t, 1H), 8.02 (d, 1H), 8.24 (d, 1H). 13C NMR (CDCl3, 100 MHz): δ 29.4, 38.8, 43.2, 55.6, 63.5, 73.9, 101.9, 122.8, 122.3, 125.4, 125.9, 126.7, 128.3, 128.4, 128.6, 131.5, 135.3, 145.8, 146.6, 151.9 MS (EI): C24H25ClO3 Exact Mass: 396.91 Observed Mass : 379.3.90 and 381.30 (chloro pattern and loss of benzylic OH).
Melting point (DSC) 132.2 ̊C.

Example 2: Synthesis of 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene (VI)
A solution of compound (V) (48 g, crude obtained as above) in toluene (246 mL) with catalytic amount of p–toluene sulfonic acid (1.8g) was stirred at 60-65 OC for 6 h under nitrogen atmosphere. Progress of the reaction was monitored over TLC. After completion of reaction, reaction mass was cooled to 25 OC and organic solvent was evaporated under reduced pressure to obtain residue. Obtained residue was suspended in 10 % aqueous solution of sodium bicarbonate and then extracted with dichloromethane (3×170 mL). Organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to crude product. Crude product was further purified by crystallization from acetonitrile (90 mL) to give 2-(4'-chloro-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1,4-dimethoxynaphthalene as a white solid (24.75 g, 65.13 mmol, 93%).
FTIR (KBr): 3041, 2925, 2895, 2838, 1623, 1593, 1488, 1459, 1441, 1407, 1393, 1371, 1352, 1265, 1225, 1165, 1100, 1087, 1011, 826, 771 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.91-2.01(m, 1H), 2.11-2.14 (m, 1H), 2.35-2.41 (m, 1H), 2.55-2.71 (m, 3H), 2.98 (t, 1H), 3.86 (s, 3H), 4.02 (s, 3H), 6.04 (s, 1H), 6.65 (s, 1H), 7.26-7.34 (m, 4H), 7.48 (t, 1H), 7.55 (t, 1H), 8.12 (d, 1H), 8.24 (d, 1H). 13C NMR (CDCl3, 100 MHz): δ 29.4, 30.3, 33.9, 39.2, 55.6, 61.5, 105.4, 122.0, 122.1, 125.1, 125.6, 126.4, 126.6, 128.3, 128.5, 128.9, 131.5, 131.6, 137.2, 145.4, 146.2, 151.5 MS (EI): C24H23ClO2 Exact Mass: 378.9 Observed Mass : 379.25 and 381.20 (chloro pattern).
PXRD [2θ] (Cu Kα1 = 1.54060 Å, Kα2 = 1.54443 Å, Kβ = 1.39225 Å; 40 mA, 45 kV):
9.27, 9.96, 10.91, 12.18, 12.40, 12.83, 13.58, 14.74, 15.70, 16.03, 16.19, 16.82, 17.48, 18.60, 19.28, 19.55, 19.99, 21.25, 21.52, 21.91, 22.61, 23.01, 23.50, 23.73, 24.28, 24.50, 24.97, 26.10, 27.03, 27.36, 28.10, 29.05, 29.60, 30.20, 30.60, 32.08, 32.55, 33.17, 34.32, 34.63, 35.69, 37.09, 37.76, 38.54, 38.91
Melting point (DSC) 144.7 ̊C.

Example 3: synthesis of 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (VII)
A solution of compound (VI) (24.1 g, 63.5 mmol) in ethyl acetate (1 L) was charged to Paar autoclave reactor, followed by Pd/C (8 g, 10 % wet). Reaction mass was stirred under hydrogen pressure (2 to 3 kg/cm2 ) at 20-25 OC for 4 h. Progress of the reaction was monitored over TLC. Pd/C was filtered over a bed of celite. Ethyl acetate was evaporated under reduced pressure to give compound (VII) as mixture of geometric isomer (23.4 g). Separation of cis and trans isomer of compound (VII) was achieved through selective crystallization in acetonitrile. Trans isomer of compound (VII) precipitated out (6.9 g) and cis isomer of compound (VII) isomer remains in solution.
Mother liquor was concentrated to obtain residue, which on crystallization from methanol gave the cis isomer of compound (VII) (10.1 g).
Trans isomer of compound (VII): FTIR (KBr): 2994, 2922, 1627, 1594, 1488, 1461, 1441, 1371, 1359, 1265, 1220, 1124, 1086, 1010, 822, 770, 668 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.70-1.83 (m, 4H), 1.99-2.08 (m, 4H), 2.67 (t, 1H), 3.30-3.35 (m, 1H), 3.92 (s, 3H), 4.03 (s, 3H), 6.72 (s, 1H), 6.65 (s, 1H), 7.23-7.32 (m, 4H), 7.46 (t, 1H), 7.54 (t, 1H), 8.05 (d, 1H), 8.23 (d, 1H). 13C NMR (CDCl3, 100 MHz): δ 34.0, 34.5, 36.6, 43.6, 55.6, 62.6, 102.4, 121.9, 122.2, 124.8, 125.2, 126.5, 128.5, 128.6, 131.5, 134.6, 145.8, 145.9, 152.0 MS (EI): C24H25ClO2 Exact Mass: 380.15 Observed Mass : 381.20 and 383.15 (chloro pattern).
Melting Point (DSC) = 175.4 OC
PXRD [2θ] (Cu Kα1 = 1.54060 Å, Kα2 = 1.54443 Å, Kβ = 1.39225 Å; 40 mA, 45 kV): 8.85, 9.92, 10.60, 12.14, 12.45, 13.50, 15.78, 16.60, 16.89, 17.18, 18.84, 19.61, 19.77, 20.42, 21.25, 22.45, 22.77, 23.27, 24.36, 25.04, 25.96, 26.71, 27.18, 2784, 28.36, 29.23, 30.05, 31.84, 34.38, 34.88
Cis isomer of compound (VII): FTIR (KBr): 2986, 2966, 2929, 2852, 1626, 1593, 1507, 1494, 1459, 1449, 1370, 1351, 1217, 1160, 1120, 1091, 1010, 994, 970, 838, 770 cm-1.
MS (EI): C24H25ClO2 Exact Mass: 380.15 Observed Mass : 381.20 and 383.15 (chloro pattern).
Melting point (DSC) 79.2 0C.

Example 4: Synthesis of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (VIII)
To a solution of ceric ammonium nitrate (57.5 g) in water (150 mL) was added a solution of compound (VII) (10.0 g) in tetahydronfuran (100 mL) at 200C and stir the reaction mixture for 3 h. Progress of the reaction was monitored over TLC. After the completion of reaction nearly 2.5-3 h, the reaction mass was extracted with ethyl acetate (2×100 mL). Combined organic layer was washed with saturated brine (100 mL). After that organic layer was separated and evaporated under reduced crude product isolated as a solid (9.2 g). Crude product further purified from DCM/Hexane mixture (1:10) to give 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione as a yellow solid (8.5 g).
Melting point (DSC) 137.7 ̊C.
FTIR (KBr): 2936, 2855, 1659, 1590, 1489, 1448, 1407, 1330, 1304, 1259, 1151, 1089, 1027, 910, 823, 775 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.42-1.50 (m, 2H), 1.62-1.71 (m, 2H), 2.01-2.12 (m, 4H), 2.58 (t, 1H), 3.01 (t, 1H), 6.04 (s, 1H), 6.80 (s, 1H), 7.22 (d, 2H), 7.29 (t, 2H), 7.72-7.77 (m, 2H), 8.06-8.15 (m, 2H).
13C NMR (CDCl3, 100 MHz): δ 26.92, 27.74, 29.81, 32.16, 33.93, 34.41, 36.21, 38.73, 43.39, 125.96, 126.00, 126.75, 126.46, 128.18, 128.46, 128.52, 128.62, 131.46, 131.68, 131.85, 131.9, 132.45, 132.53, 133.13, 133.67, 133.71, 134.11, 143.50, 145.28, 155.17, 155.64, 184.74, 184.90, 185.33, 185.50;
MS (EI): C22H19ClO2 Exact Mass: 350.11 Observed Mass : 351.20 and 353.15 (chloro pattern).

Example 5: Synthesis of 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (IX)
Sodium carbonate (2.79 g) and de-mineralized water 30 mL was charged to reactor. Added 30% aqueous hydrogen peroxide solution (25mL) and stirred the reaction mass for 15 min. Added solution of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (8.4 g) in dioxane 30 mL. The reaction mass was stirred at 75-80 OC. If required added more amount of hydrogen peroxide at that temperature. The reaction mass was stirred for 2 hrs. Cooled the flask and reaction was extracted with 3*60 mL EtOAc. Combined EtOAc was washed with saturated brine (100 mL). Solvent was distilled out, to give compound (IX) (8.5.g).
FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451, 1306, 1287, 1157, 1089, 944, 886, 801, 725 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.28-1.41 (m, 2H), 1.56-1.62 (t, 2H), 1.9 (s, 4H), 3.96 (s, 1H) 7.16-7.18(d, 2H), 7.28-7.29 (d, 2H), 7.76-7.78 (t, 2H) 7.97-7.98 (d,2H), 8.03-8.05 (d,2H) ;13C NMR (CDCl3, 100 MHz): δ 26.6, 29.3, 33.3, 33.4, 34.3, 37.7, 43.3, 57.7, 58.2, 66.3, 66.9, 126.5, 126.6, 127.6, 128.4, 128.5, 131.5, 131.6, 132.8, 134.3, 134.6, 143.2, 145.2, 191.5, 192.1
Melting point (DSC) 155.0 ̊C.

Example 6: Process for synthesis of Atovaquone
1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (10 g) was added to reactor. DCM (10.0 mL) and water (4.0 mL) was added to it. Added drop wise conc. Sulphuric acid (30.0 mL). The brown to black suspension was stirred over-night. The suspension was charged to 200 mL cold water. Crude product mixture obtained was extracted with 3X90 mL DCM. Combined DCM layer was treated with charcoal (1.5 g). Inorganic mass was removed by passing over bed of Celite. Solvent was distilled out of to give crude product. Crude product was re-crystalized from Acetonitrile to obtain compound (I) of 99% HPLC purity (7.5 g).
FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm-1.
1H NMR (CDCl3, 400 MHz): δ 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m, 2H), 2.63 (t, 1H), 3.16 (t, 1H), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, 1H), 7.68 (t, 1H), 7.76 (t,1H), 8.07 (d, 1H), 8.13 (d, 1H); 13C NMR (CDCl3, 100 MHz): δ 29.18, 34.34, 34.46, 34.64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02, 146.05, 152.98, 181.80, 184.56; MS (EI): C22H19ClO3: 366.1023; [M+Na]+: 388.95, [M-H]-: 365.30;
Melting Point at 218.5- 220.2 0C (20C/min)
PXRD [2θ] (Cu Kα1 = 1.54060 Å, Kα2 = 1.54443 Å, Kβ = 1.39225 Å; 40 mA, 45 kV): 7.30, 9.70, 10.79, 11.11, 11.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68, 25.35, 26.18, 26.84, 28.52, 28.70, 29.52, 30.68, 34.23, 36.84.

Example 7: Synthesis of 4-(4-chlorophenyl)-1-(1,4-dimethoxynaphthalen-2-yl)cyclohexanol (V) (Grignard method)
Magnesium metal (0.3 g, 12.5 mmol) was charged to reactor. Added THF (10 mL) to it. 2-Bromo-1,4-dimethoxynaphthalene (5.0 g, 18.72 mmol) in 25 mL THF was added dropwise under nitrogen atmosphere over 10 min interval. Reaction mass was stirred at 25 OC for 2.5 h. Added drop wise 4-(4-chlorophenyl)cyclohexanone ( 3.9 g, 18.72 mmol) in THF (40 mL). The reaction mass was stirred for 1 h at 20 ̊C. The reaction was quenched with 10 % ammonium chloride solution (50 mL) at 0-10 ̊C, stripped off, volatile matter under reduced pressure. Crude product was extracted with EtOAc 3*15 mL. EtOAc layer separated and distilled out volatile matter under reduced pressure over rotary evaporator to give crude product as viscous oil (7.5 g). The product was confirmed against standard sample on TLC.

Example 8: Synthesis of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)-1,4-dimethoxynaphthalene (X)
To a solution of compound (VII) (7.6 g) in dichloromethane was added catalytic amount of iron powder (0.2 g) and cooled to 0 0C. A solution of bromine (3.52 g) in dichlormethane (25 mL) was slowly added at 0 0C and stirred for 3 h at 0 0C. Progress of reaction was monitored on TLC and after completion of reaction; aqueous solution of sodium carbonate (10%) was added. Organic layer was dried over anhydrous sodium suflate and concentrated under reduced pressure to obtain crude compound (X) (10.1 g).

Example 9: Synthesis of 2-bromo-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XI)
To a solution of ceric ammonium nitrate (21.98 g) in water (150 mL) was added a solution of compound (X) obtained in example 8 (10.0 g) in tetahydronfuran (100 mL) at 200C and stir the reaction mixture for 3 h. Progress of the reaction was monitored over TLC. After the completion of reaction nearly 2.5-3 h, the reaction mass was extracted with ethyl acetate (2×100 mL). Combined organic layer was washed with saturated brine (100 mL). After that organic layer was separated and evaporated under reduced crude product isolated as a solid (9.2 g). Crude product further purified from DCM/Hexane mixture (1:10) to give crude compound (XI) as a yellow solid (8.0 g).
Example 10: Synthesis of compound (I) from compound (XI)

To a solution of crude compound (XI) (8.0g) in tetrahydrofurane was added methanolic solution of potassium hydroxide (3 g) and resulted mixture was stirred for 24 h at 400C. After completion of reaction, solvent was evaporated under reduced pressure to obtain crude material. Crude material was suspended in DCM (10.0 mL) and water (4.0 mL) was added to it. Added drop wise conc. Sulphuric acid (30.0 mL). The brown to black suspension was stirred over-night. The suspension was charged to 200 mL cold water. Crude product mixture obtained was extracted with 3X90 mL DCM. Combined DCM layer was treated with charcoal (1.5 g). Inorganic mass was removed by passing over bed of Celite. Solvent was distilled out of to give crude product. Crude product was re-crystalized from Acetonitrile to obtain compound (I) of 99% HPLC purity (4.5 g).